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.

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.

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.

Gadolinium deposition and the potential for toxicological sequelae - A literature review of issues surrounding gadolinium-based contrast agents.

Every year, approximately 30 million magnetic resonance imaging scans are enhanced with gadolinium-based contrast agents (GBCAs) worldwide. Although the development of nephrogenic systemic fibrosis in patients with renal impairment is well-documented, over recent years it has become apparent that exposure to GBCAs can potentially result in gadolinium deposition within human bone and brain tissue even in the presence of normal renal function. This review will address some of the controversies surrounding the safety of GBCA administration based on evidence from in vivo experiments, animal studies and clinical studies. We additionally evaluate the potential risk of toxicity from exposure to gadolinium in light of new guidance published by the US Food and Drug Administration and the European Medicines Agency, and discuss whether gadolinium deposition disease exists as a new diagnosis.

An assessment of the variation in the concentration of acetylcysteine in infusions for the treatment of paracetamol overdose.

BACKGROUND: Intravenous acetylcysteine is the treatment of choice for paracetamol poisoning. A previous UK study in 2001 found that 39% of measured acetylcysteine infusion concentrations differed by >20% from anticipated concentrations. In 2012, the UK Commission on Human Medicines made recommendations for the management of paracetamol overdose, including provision of weight-based acetylcysteine dosing tables. The aim of this study was to assess variation in acetylcysteine concentrations in administered infusions following the introduction of this guidance. METHODS: A 6-month single-centre prospective study was undertaken at a UK teaching hospital. After preparation, 5-ml samples were taken from the first, second and third/any subsequent acetylcysteine infusions. Acetylcysteine was measured in diluted (1:50) samples by high-performance liquid chromatography. Comparisons between measured and expected concentrations based on prescribed weight-based dose and volume were made for each infusion. RESULTS: Ninety samples were collected. There was a variation of ≤10% in measured compared to expected concentration for 45 (50%) infusions, of 10-20% for 27 (30%) infusions, 20.1-50% for 14 (16%) infusions and >50% for four (4%) infusions. There was a median (interquartile range) variation in measured compared to expected concentration of -3.6 mg ml-1 (-6.7 to -2.3) for the first infusion, +0.2 mg ml-1 (-0.9 to +0.4) for the second infusion and -0.3 mg ml-1 (-0.6 to +0.2) for third and fourth infusions. CONCLUSION: There has been a moderate improvement in the variation in acetylcysteine dose administered by infusion. Further work is required to understand the continuing variation and consideration should be given to simplification of acetylcysteine regimes to decrease the risk of administration errors.

Outcomes from massive paracetamol overdose: a retrospective observational study.

LINKED ARTICLE: This article is commented on by Bateman DN and Dear JW. Should we treat very large paracetamol overdose differently? Br J Clin Pharmacol 2017; 83: 1163-5. https://doi.org/10.1111/bcp.13279 AIMS: Treatment of paracetamol (acetaminophen) overdose with acetylcysteine is standardized, with dose determined only by patient weight. The validity of this approach for massive overdoses has been questioned. We systematically compared outcomes in massive and non-massive overdoses, to guide whether alternative treatment strategies should be considered, and whether the ratio between measured timed paracetamol concentrations (APAPpl ) and treatment nomogram thresholds at those time points (APAPt ) provides a useful assessment tool. METHODS: This is a retrospective observational study of all patients (n = 545) between 2005 and 2013 admitted to a tertiary care toxicology service with acute non-staggered paracetamol overdose. Massive overdoses were defined as extrapolated 4-h plasma paracetamol concentrations >250 mg l-1 , or reported ingestions ≥30 g. Outcomes (liver injury, coagulopathy and kidney injury) were assessed in relation to reported dose and APAPpl :APAPt ratio (based on a treatment line through 100 mg l-1 at 4 h), and time to acetylcysteine. RESULTS: Ingestions of ≥30 g paracetamol correlated with higher peak serum aminotransferase (r = 0.212, P < 0.0001) and creatinine (r = 0.138, P = 0.002) concentrations. Acute liver injury, hepatotoxicity and coagulopathy were more frequent with APAPpl :APAPt  ≥ 3 with odds ratios (OR) and 95% confidence intervals (CI) of 9.19 (5.04-16.68), 35.95 (8.80-158.1) and 8.34 (4.43-15.84), respectively (P < 0.0001). Heightened risk persisted in patients receiving acetylcysteine within 8 h of overdose. CONCLUSION: Patients presenting following massive paracetamol overdose are at higher risk of organ injury, even when acetylcysteine is administered early. Enhanced therapeutic strategies should be considered in those who have an APAPpl :APAPt  ≥ 3. Novel biomarkers of incipient liver injury and abbreviated acetylcysteine regimens require validation in this patient cohort.

MDMB-CHMICA: Availability, Patterns of Use, and Toxicity Associated With This Novel Psychoactive Substance.

BACKGROUND: MDMB-CHMICA (methyl 2-[[1-(cyclohexylmethyl)indole-3-carbonyl]amino]-3,3-dimethylbutanoate) is a synthetic cannabinoid receptor agonist that has been detected in several recreational drug products in Europe since August 2014. OBJECTIVES: This article aims to describe the prevalence of use, availability, and desired and adverse effects of MDMB-CHMICA. METHODS: Data were collated from published scientific literature, and systematic searches were conducted of publically available Internet sources (the "gray literature"), including websites offering to sell MDMB-CHMICA and Internet discussion forums featuring user reports. RESULTS: There are two case reports of fatalities in the published literature and one series of analytically confirmed cases of intoxication with MDMB-CHMICA. Seventy-eight websites offered to sell MDMB-CHMICA and a range of quantities were available with discounts for purchase of larger quantities (from 0.25 g at $27.95/g to 100 kg at $1.28/g). We identified 36 reports from MDMB-CHMICA users on Internet discussion forums dated October 2014 onwards. The most common positive effect reported by users was euphoria (11; 30.6%) and almost all reports (33; 91.7%) described one or more adverse effects, most commonly palpitations (11; 30.6%), vomiting (9; 25.0%), loss of consciousness (6; 16.7%), visual hallucinations (6; 16.7%), chest pain (5; 13.9%), and anxiety (5; 13.9%). CONCLUSIONS: This systematic review of qualitative and scientific data relating to MDMB-CHMICA shows that it is widely available from Internet-based suppliers. Users describe a spectrum of effects that are consistent with other synthetic cannabinoids, but there was a high prevalence of adverse effects, and both users and suppliers warn of its high potency.

Delays during the administration of acetylcysteine for the treatment of paracetamol overdose.

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.

Ethylphenidate: availability, patterns of use, and acute effects of this novel psychoactive substance.

PURPOSE: Ethylphenidate is a novel psychoactive substance that is an analogue of methylphenidate. This paper describes its availability, patterns of use, and acute effects. METHODS: Searches of the scientific and grey literature (publicly accessible Internet resources) were undertaken, using the keywords "Ethylphenidate", "Ethyl phenidate", "Ethyl phenyl(piperidin-2-yl)acetate", and "Nopaine", to identify information on the prevalence and patterns of use, desired effects, and toxicity of ethylphenidate. An Internet snapshot survey was performed on 10 February 2015 to provide information on availability and cost of ethylphenidate. RESULTS: The literature search identified 1 case series of acute recreational ethylphenidate toxicity, 1 case report of ethylphenidate dependence, 1 qualitative analysis of user reports on Internet drug forums, 2 conference abstracts for surveillance studies, 1 report of two cases of ethylphenidate detected in post-mortem analyses, and 198 user reports on Internet discussion forums and social media sites. The Internet snapshot survey found 83 websites selling ethylphenidate, with purchase prices ranging from £28.20 ± 0.63 (€37.71 ± 0.85) per gram for a 500-mg amount to £2.64 ± 0.57 (€3.53 ± 0.77) per gram for 1 kg. The published cases and Internet user reports suggest the acute effects of ethylphenidate are similar to other stimulant drugs; the most common route of use was by nasal insufflation. The most common desired effects were euphoria, stimulation, and increased concentration, sociability, and energy levels; the most common unwanted effects included anxiety, palpitations, insomnia, and paranoia. CONCLUSION: This review of the scientific and grey literature has demonstrated that the acute harms associated with its use are stimulant in nature and that ethylphenidate is widely available to users over the Internet, with significant discounts for bulk purchases.

Safety of metformin in patients with chronic obstructive pulmonary disease and type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is commonly associated with chronic obstructive pulmonary disease (COPD). Metformin is a valuable treatment for T2DM, and may offer additional benefits in COPD. However, due to its rare association with lactic acidosis, its safety in COPD is uncertain. We retrospectively identified patients with T2DM who had been admitted to hospital for COPD exacerbations. We compared those who were taking metformin with those who were not, with respect to their lactate concentration (primary endpoint) and survival (secondary endpoint). The study cohort (n = 130) had a mean (±standard deviation) age of 73.0 ± 9.8 years and 47 (36%) were female. Arterial blood gases were recorded in 120 cases: 88 (73%) were hypoxemic, 45 (38%) were in respiratory failure and 33 (28%) had respiratory acidosis. The 51 patients (39%) in the metformin group had a median (interquartile range) lactate concentration of 1.45 mmol/L (1.10-2.05) versus 1.10 mmol/L (0.80-1.50) in the non-metformin group (p = 0.012). Median survival was 5.2 years (95% CI 4.5-5.8) versus 1.9 years (1.1-2.6), respectively (hazard ratio 0.57; 95% CI 0.35-0.94). This remained significant in a multivariate model adjusted for measurable confounders. In conclusion, among patients with COPD at high risk for lactate accumulation, metformin therapy was associated with a minor elevation of lactate concentration of doubtful clinical significance. Metformin was associated with a survival benefit, but this must be interpreted cautiously due to possible effects from unmeasured confounders. Viewed collectively, the results suggest that COPD should not present a barrier to the investigational or clinical use of metformin.

Safety of Metformin in Patients with Chronic Obstructive Pulmonary Disease and Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is commonly associated with chronic obstructive pulmonary disease (COPD). Metformin is a valuable treatment for T2DM, and may offer additional benefits in COPD. However, due to its rare association with lactic acidosis, its safety in COPD is uncertain. We retrospectively identified patients with T2DM who had been admitted to hospital for COPD exacerbations. We compared those who were taking metformin with those who were not, with respect to their lactate concentration (primary endpoint) and survival (secondary endpoint). The study cohort (n = 130) had a mean (±standard deviation) age of 73.0 ± 9.8 years and 47 (36%) were female. Arterial blood gases were recorded in 120 cases: 88 (73%) were hypoxemic, 45 (38%) were in respiratory failure and 33 (28%) had respiratory acidosis. The 51 patients (39%) in the metformin group had a median (interquartile range) lactate concentration of 1.45 mmol/L (1.10-2.05) versus 1.10 mmol/L (0.80-1.50) in the non-metformin group (p = 0.012). Median survival was 5.2 years (95% CI 4.5-5.8) versus 1.9 years (1.1-2.6), respectively (hazard ratio 0.57; 95% CI 0.35-0.94). This remained significant in a multivariate model adjusted for measurable confounders. In conclusion, among patients with COPD at high risk for lactate accumulation, metformin therapy was associated with a minor elevation of lactate concentration of doubtful clinical significance. Metformin was associated with a survival benefit, but this must be interpreted cautiously due to possible effects from unmeasured confounders. Viewed collectively, the results suggest that COPD should not present a barrier to the investigational or clinical use of metformin.

Intravenous lipid emulsion interference in coagulation testing: an ex vivo analysis.

INTRODUCTION: Intravenous lipid emulsion is used in the rescue treatment of certain poisonings. A complication is interference with laboratory analyses. The aim of this study was to determine the impact of intravenous lipid emulsion on routine laboratory analysis of coagulation parameters ex vivo and determine if any of the analytical techniques remain reliable. METHODS: Samples were obtained from 19 healthy volunteers and divided in triplicate. One sample served as a control, and the other two were diluted to simulate the treatment of an average adult with Intralipid® 20 per cent Fresenius Kabi 100 mL (dilution-1) or 500 mL (dilution-2). Coagulation tests performed were prothrombin time, activated prothrombin time, D-dimer concentration and fibrinogen. Coagulation testing was performed by three techniques. Test-1 was performed on a Sysmex CN6000 analyzer. Test-2 was performed with a manual mechanical endpoint method using the semi-automated Stago KC4 Delta. Test-3 involved high-speed centrifugation before repeat testing on the Sysmex CN6000 analyzer. RESULTS: For test-1, only nine (47 per cent) samples in dilution-1 could be analyzed for coagulation tests, and no coagulation tests could be analyzed for dilution-2 because of lipaemia. For test-2 and test-3, all samples could be analyzed, and all results of both testing methods fell within the limits of the laboratory reference range. DISCUSSION: Difficulties in laboratory analysis of patients having received intravenous lipid emulsion are due to multiple factors. Most automated coagulation analyzers use optical measurements, which can be unreliable in the presence of a high intravenous lipid concentration. By altering the lipaemia in the testing solution using high-speed centrifugation or by using manual mechanical endpoint detection, we were able to obtain reliable results. These findings are limited by the use of an ex vivo method and healthy volunteers. CONCLUSIONS: This ex vivo model confirms that Intralipid® interferes with routine coagulation studies. It is important that clinicians are aware and inform their laboratories of its administration.

E-cigarette or vaping-associated lung injury (EVALI): a review of international case reports from outside the United States of America.

INTRODUCTION: E-cigarette or vaping-associated lung injury has been reported extensively throughout the United States without a corresponding number of international cases. Cannabinoid-based products have been implicated in the majority of cases. OBJECTIVES: To collate published reports of E-cigarette or vaping-associated lung injury outside the United States and to identify the reasons behind the discrepancy in reported cases between the United States and the international community. METHODS: PubMed and Healthcare Databases Advanced Search were used to identify published case reports of E-cigarette or vaping-associated lung injury prior to February 2021 using the search terms "e-cigarette", "e-cigarettes", "vaping", "vape" and, "lung injury", "pulmonary", "respiratory". Cases occurring in the United States were excluded. Non-United States case reports were excluded if they did not meet the Centers for Disease Control and Prevention "probable case" criteria. This requires use of a vaping device within 90 days of symptom onset, the presence of pulmonary infiltrates on plain film chest radiography or ground glass opacities on computerised tomography, clinical suspicion that infection was not the underlying cause of lung injury, and the absence of other plausible medical processes to account for the presentation. Patient demographics, nature of exposure, symptomatology and outcome were compared to 125 cases from three regional United States based case series, which were chosen on the basis of having complete data for these comparative factors. RESULTS: Seventeen international cases from 13 countries were identified for analysis. There was a male predominance in both non-United States and United States cohorts (76% vs 58-83%), with a marginally higher median patient age in non-United States cases (31 vs 27, 19, 27 years). Reported use of nicotine/flavoured e-liquids was more common in non-United States cases (100% vs 58-67%), and use of cannabinoid-based products was less common (24% vs 78-92%). The most common symptoms across all cohorts were shortness of breath (76% vs 85-91%), cough (59% vs 78-83%) and fever (47% vs 78-83%). The majority of patients were hypoxic (76% vs 69-86%) and required hospital admission (88% vs 90-94%). Fewer of the non-United States patients required intensive care admission (24% vs 55-67%) though their median length of stay was longer (15 days vs 5, 6, 7 days). DISCUSSION: Uniformity amongst non-United States cases in regards to nicotine based and/or flavoured e-liquid exposure may underestimate the role of these substances in e-cigarette or vaping-associated lung injury. This is consistent with prior United States based research demonstrating increased presentations to emergency departments prior to the recognised "outbreak" of e-cigarette or vaping-associated lung injury at a time of increased nicotine based e-liquid uptake. A longer length of hospital stay, lower rate of intensive care admission and a higher rate of bronchoscopy in the non-United States cohort could be indicative of clinician inexperience internationally. It is unclear why the non-United States cases also had a lower incidence of gastrointestinal symptoms however this may also be explained by poorer diagnostic awareness. CONCLUSIONS: E-cigarette or vaping-associated lung injury is not limited to cannabinoid-based products. Apparent similarities in patient demographics, clinical features, and clinical course between non-United States and United States cases raise concern for underreporting of E-cigarette or vaping- associated lung injury internationally.

Cold water extraction of codeine/paracetamol combination products: a case series and literature review.

Introduction: Tampering with opioid containing medications for use other than their prescribed indication is well documented; however, the published literature has concentrated on stronger, prescription opioids. Less potent opioids, such as codeine, are available without prescription in many European countries in the form of combination analgesic products and these can also be altered, with reports in particular of "cold-water extraction" being a tampering method achievable using household kitchen equipment.Methods: We searched a database of patients attending two South London emergency departments for cases of self-reported ingestion of the products of cold-water extraction, with subsequent review of their case notes. We searched the scientific and grey literature to identify current knowledge of this technique.Results: We identified seven presentations in six patients, none of whom developed paracetamol toxicity or had concentrations suggesting ingestion of a significant dose of paracetamol. A review of the scientific literature on the method also demonstrated that the technique reduces recovered paracetamol in experimental laboratory settings. Additionally, the established literature characterizes the use of codeine in a recreational setting and reports one fatality associated with the method. Review of grey literature user-forums further describes recreational codeine use in relation to the method and frequent adverse events including hospital admission for paracetamol toxicity.Discussion: Whilst the method appears capable of providing a recreational dose of codeine with reduction in the recovered paracetamol, it cannot be considered safe. Pharmaceutical production methods have been successfully developed to prevent tampering through other means but none thus far have been directed at the cold water extraction technique.Conclusions: Clinicians should be aware of the potential toxicity from tampered nonprescription analgesics. There is also the need for public health education regarding the potential risks associated with these methods.

Establishing Reference Intervals for Gadolinium Concentrations in Blood, Plasma, and Urine in Individuals Not Previously Exposed to Gadolinium-Based Contrast Agents.

OBJECTIVES: Over the recent years, there have been increasing concerns that exposure to gadolinium-based contrast agents (GBCAs) may be associated with retention of Gd within the skin, bones, and solid organs in patients with normal renal function, although the clinical implications of this deposition remain to be established. There are no published data available to guide the development of reference intervals for Gd concentrations in biological samples from healthy people. The aims of this study were to (1) determine whether healthy individuals who have not received GBCAs have detectable concentrations of Gd in their blood and urine, and (2) to develop a reference range for Gd concentrations in blood and spot urine samples for healthy individuals. MATERIALS AND METHODS: Whole blood, plasma, and spot urine samples were taken from 120 healthy volunteers with estimated glomerular filtration rate 70 mL/min per 1.73 m or greater. Gd concentrations were measured in these samples using inductively coupled plasma mass-spectrometry. The reference intervals for Gd concentrations in whole blood, plasma, and urine were estimated as the 2.5th percentile and the upper reference limit as the 97.5th percentile. RESULTS: Ten (8.33%) of the 120 subjects had detectable concentrations of Gd in their whole blood (n = 5) or spot urine (n = 5) samples; no subjects had detectable concentrations of Gd in their plasma samples. Our proposed reference intervals for Gd are as follows: whole blood, <0.008 ng/mL or <0.050 nmol/L; plasma, <0.009 ng/mL or <0.057 nmol/L; spot urine, <0.036 µg/g or <0.0250 nmol/mmol. CONCLUSIONS: The results of this study provide reference intervals for whole blood, plasma, and urine Gd concentrations in healthy subjects who have not previously received GBCAs and will assist clinicians in assessing patients who have concerns regarding potential Gd retention postexposure and help guide further clinical studies to explore the pharmacokinetics of GBCAs in patients with normal renal function.

Quantification of cocaine and cocaine metabolites in dried blood spots from a controlled administration study using liquid chromatography-tandem mass spectrometry.

Cocaine is a common illicit stimulant and is mainly metabolized by hydrolysis to benzoylecgonine (BE) and ecgonine methyl ester (EME), but also to minor metabolites like norcocaine, or hydroxy-BE. When ethanol is present, cocaethylene is formed. Dried blood spot (DBS) sampling is a minimally invasive microsampling technique with possible advantages for analyte stability and ease of storage, making it an attractive matrix in forensic and clinical settings. We developed a liquid chromatography-tandem mass spectrometry-based (LC-MS/MS) method for quantifying cocaine, BE, EME, norcocaine, hydroxy-BE, and cocaethylene in DBS. Six-mm punches were extracted with aqueous buffer followed by protein precipitation, evaporation and reconstitution in mobile phase. Separation was achieved on a Polar-RP column (Phenomenex) in a 6-minute gradient including baseline-separation of norcocaine and BE. For MS detection, a QTRAP 5500 (Sciex) was used in positive electrospray ionization (ESI) multiple reaction monitoring (MRM) mode. The method was validated for selectivity, sensitivity [lower limited of quantification (LLOQ) 1.0-5.0 ng/mL], imprecision (≤13.4%, ≤19.6% at LLOQ), accuracy (≤ ± 14.9%), matrix effects, extraction efficiency (≥20.9%), hematocrit effect, volume spotted, punch location, long-term and autosampler stability. Concentrations in DBS from a controlled cocaine administration study in healthy volunteers were compared to whole blood and plasma. Although concentrations correlated moderately to strongly (Spearman's ρ 0.603-0.958), agreement between paired samples was poor, with overestimation of DBS concentrations and wide confidence intervals in Bland-Altman analysis. A possible cause are differences in capillary and venous blood concentrations, with the underlying mechanism requiring further research before DBS analysis for cocaine and its metabolites can be considered equivalent to whole blood or plasma analysis.

Change in the new psychoactive substances associated with Emergency Department acute toxicity presentations associated with the introduction of the UK 2016 Psychoactive Substances Act.

OBJECTIVES: In May 2016, the Psychoactive Substances Act (PSA) came into effect in UK making it an offence to produce or supply new psychoactive substances (NPS). The aim of this study was to determine whether this was associated with a change in Emergency Department (ED) presentations with acute NPS toxicity. METHOD: ED presentations to our inner-city hospital in London, UK, with acute NPS toxicity in the 12 months before and after the PSA introduction [June 2015-May 2016 (2015/2016) and June 2016-May 2017 (2016/2017)] were obtained from our database. The following data were extracted: (i) demographics; (ii) NPS(s) self-reported [categorized as synthetic cannabinoids (SC), cathinones, and "other NPS")]; and (iii) month of presentation. RESULTS: There were 1884 presentations with recreational drug toxicity, 447 (23.7%) involved NPS. There was no difference in the overall proportion of presentations involving an NPS in 2015/2016 [n = 196 (22.3%)] and 2016/2017 [251 (24.9%); (p = .48)]. There were a mean ± SD of 16.3 ± 3.7 NPS-related presentations per month in 2015/2016 and 20.9 ± 9.2 in 2016/2017; there was no significant change in overall monthly NPS-related presentations between these periods (p = .15). However, mean ± SD monthly SC-related presentations increased from 2015/2016 (5.9 ± 2.5) to 2016/2017 (17 ± 9.8); p = .004. Mean monthly cathinone-related presentations decreased from 2015/2016 (8.8 ± 4.2) to 2016/2017 (3.8 ± 2.7); p = .001. There was no significant change in monthly mean "other NPS" presentations from 2015/2016 (1.8 ± 2.2) to 2016/2017 (0.5 ± 0.8); p = .062. Between 2015/2016 and 2016/2017, SCs as a proportion of NPS-related presentations increased (r = .90) whilst cathinones decreased (r = -0.82). CONCLUSION: NPS present front-line health services with unique challenges, and the PSA 2016 represents a major legislative effort in UK to limit their availability and supply. The burden of NPS use on this inner-city ED remains large 12 months after this legislation has come into force, with evolving patterns of NPS use.

Detection of cocaine and its metabolites in whole blood and plasma following a single dose, controlled administration of intranasal cocaine.

The disposition of drugs and their metabolites have been extensively described in the literature, based primarily on the analysis of plasma and urine. However, there are more limited data on their disposition in whole blood, which is often the only specimen available in forensic investigations and cases of driving under the influence of drugs. In this study, we have, for the first time, established pharmacokinetic properties of cocaine (COC) and its metabolites from concurrently collected whole blood and plasma samples, following a single 100 mg dose of cocaine hydrochloride administered via nasal insufflation to seven healthy volunteers. The median Cmax of COC and its major metabolites, benzoylecgonine (BZE) and ecgonine methyl ester (EME), were closely related in whole blood and plasma. The median Cmax for COC in plasma was 379.7 ng/mL (347.5-517.7) and 344.24 ng/mL (271.6-583.2) in whole blood. The median Cmax for BZE in plasma was 441.2 ng/mL (393.6-475. and 371.18 ng/mL (371.1-477.3) in whole blood, EME was 105.5 ng/mL (93.6-151.8) in plasma and 135.5 ng/mL (87.8-183) in whole blood. Calculated medians of the whole blood to plasma ratio of COC (0.76), BZE (0.98) and EME (1.02) of approximately 1, strongly suggesting that the erythrocyte cell wall presents no barrier to COC and its metabolites. Furthermore, whole blood and plasma concentrations of COC were strongly correlated (R2  = 0.0914 R = 0.956, p < 0.0001), as was BZE (R2  = 0.0932 R = 0.965, p < 0.0001) and EME (R2  = 0.0964R = 0.928, p < 0.0001). The minor oxidative metabolite norcocaine (NCOC) was detected in both whole blood and plasma at concentrations between 1 and 5 ng/mL within 60-180 minutes, suggesting that NCOC could be indicator of recent COC administration. Data from this study have shown for the first time that COC and its metabolites BZE and EME are evenly distributed between plasma and whole blood following controlled single-dose intranasal COC administration.