Publications by authors named "Paul I Dargan"

182 Publications

National audit of antidote stocking in UK emergency departments.

Eur J Hosp Pharm 2021 Jul 13;28(4):217-222. Epub 2019 Jul 13.

Department of Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Background: Previous audits of antidote stocking in UK hospitals have demonstrated variable but improving compliance with joint Royal College of Emergency Medicine and National Poisons Information Service guidance on antidote availability in emergency departments. The guidance was updated in 2017.

Aim: To provide a current picture of compliance with the 2017 antidote guidance and compare this to previous audits.

Methods: Questionnaires were distributed to all hospitals in the UK with an emergency department via medicines information and regional pharmacy procurement networks. Data were collected on availability and stock levels of category A (immediately available) and category B (available within 1 hour) antidotes. Additionally, data were collected on holdings of category C (held supra-regionally) antidotes and arrangements for sourcing these if not stocked locally.

Results: 233 hospitals were surveyed and 178 replies (76.4%) were received. There were 73 hospitals (41.7%) fully compliant with guidance for category A, 34 hospitals (19.1%) for category B and 18 hospitals (10.1%) for both categories A and B antidotes. Few hospitals stocked category C antidotes (1.1%-34.8%). Evidence of formalised regional holding arrangements for category C antidotes, as advised in the guidance, was noted in some areas but many regions remain without such agreements.

Conclusions: Most hospitals remain not fully compliant with stocking recommendations for categories A and B antidotes, with limited recent improvement. Category C antidotes are stocked by few hospitals although awareness of where these can be sourced appears to be increasing. Emergency departments should review their antidote stocking arrangements to ensure compliance with guidance. Formal arrangements for stocking of the more rarely used category C antidotes at a regional level are also required, where not already in existence, in order to assure their availability in an equitable way across the country.
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http://dx.doi.org/10.1136/ejhpharm-2019-001988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239273PMC
July 2021

Gadolinium Concentrations in Biological Matrices From Patients Exposed to Gadolinium-Based Contrast Agents.

Invest Radiol 2021 Jul;56(7):458-464

Viapath Analytics, King's College Hospital NHS Foundation Trust.

Objectives: There is increasing evidence that Gd may be retained within the skin, bones, and solid organs in patients with normal renal function after exposure to Gd-based contrast agents (GBCAs). Here we present clinical data from 19 patients who requested referral to our clinical toxicology service for assessment of potential "Gd toxicity."

Materials And Methods: Patients had undergone a median of 2 (interquartile range [IQR], 1-5) exposures to GBCAs and were reviewed at a median of 5 months (IQR, 2-8 months) after the last GBCA exposure. Patients had a clinical assessment by a clinical toxicologist, and biological samples were taken in 17 patients (89.5%). Gd concentrations were measured in these samples using inductively coupled plasma mass spectrometry.

Results: All patients had significant comorbidities, and after an extensive clinical review, none of the reported symptoms were considered likely to be related to "Gd toxicity." Whole blood, plasma, and urine samples had detectable Gd concentrations in 69.2%, 78.6%, and 95.2% of samples, respectively. Median (IQR) concentrations of Gd were as follows: whole blood, 0.013 ng/mL (IQR, limit of detection [LOD]-0.884 ng/mL); plasma, 0.012 ng/mL (IQR, LOD-0.046 ng/mL); and spot urine, 0.304 μg/g creatinine (IQR, 0.070-3.702 μg/g creatinine). There were positive correlations between whole blood and plasma (P = 0.0024, r = 0.84), whole blood and urine (P = 0.0018, r = 0.82), and plasma and urine (P = 0.0001, r = 0.89) Gd concentrations. There was a negative correlation between Gd concentrations and the period after exposure for whole blood (P = 0.0028, r = -0.80), plasma (P = 0.0004, r = -0.86), and urine (P < 0.0001, r = -0.91).

Conclusions: We identified detectable Gd concentrations in biological matrices from all patients reporting exposure to GBCAs who were reviewed in our clinical toxicology outpatient clinic with concerns regarding potential "Gd toxicity"; however, there were no clinical features of toxicity present in this cohort. Further research is required to explore the pharmacokinetics and pharmacodynamics of GBCAs in patients with normal renal function and to determine the clinical significance of these detectable Gd concentrations.
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http://dx.doi.org/10.1097/RLI.0000000000000762DOI Listing
July 2021

Non-medical Use of Prescription Gabapentinoids (Gabapentin and Pregabalin) in Five European Countries.

Front Psychiatry 2021 28;12:676224. Epub 2021 Apr 28.

Hospital del Mar, Institut de Neuropsiquiatria i Addiccions (INAD), Barcelona, Spain.

Non-medical use (NMU) of prescription GABA analogs (pregabalin and gabapentin) has been reported especially in opiate dependent persons. However, by now the prevalence of NMU of gabapentinoids in the general population has not been sufficiently evaluated. The aim of this research paper is to determine the prevalence of prescription GABA analog NMU and associated demographics in five European countries with special detail of Spain. The RADARS Survey of Non-Medical Use of Prescription Drugs Program (NMURx) is a harmonized series of contemporaneous cross-sectional surveys of adults conducted in multiple countries. NMURx collects data from the general population in each participating country about NMU of prescription drugs, illicit drugs, and associated demographics. NMU was defined as "using a medication without a doctor's prescription or for any reason other than what was recommended by their doctor." Responses from Spain (4Q2017, =10,062) were analyzed in detail. Comparative data were available from France, Germany, Italy, and UK. Responses were collected using non-probability quota sampling and post-stratification population weighting was applied to reflect the national distributions of adults, based on age, gender, and census region. Rates of NMU and associated demographics were reported as rate of past 90-day NMU per 100,000 adult population with 95% confidence intervals. Germany (1,197 per 100,000 adult population [95% CI: 1,004.3-1,379.1]) and United Kingdom (1,067 per 100,000 adult population [95% CI: 851.3-1,283.2]) presented the highest prevalence of gabapentinoids NMU. In Spain the prevalence of past 90 days GABA analog NMU was: 344.4, 95% (CI 204.8-484.0), with male predominance. Those who non-medically use GABA analogs had a higher prevalence of lifetime chronic pain, lifetime illicit drug use, and previous substance abuse treatment. In Spain, 20% of respondents who ever have used gabapentinoids, reported a lifetime NMU; the prevalence was higher for pregabalin 624 (6.2%) than for gabapentin 444 (4.4%). The main reasons for use were to self-treat pain and other medical conditions. The risk of NMU of gabapentinoids should not be neglected. Subjects with a history of chronic pain and lifetime substance use disorders had an increased risk of NMU of gabapentinoids.
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http://dx.doi.org/10.3389/fpsyt.2021.676224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113698PMC
April 2021

Acute toxicity from the synthetic cathinone -ethylpentylone (ephylone) in the United Kingdom.

Clin Toxicol (Phila) 2021 Apr 15:1-4. Epub 2021 Apr 15.

NIHR Health Protection Research Unit for Chemical Threats and Hazards, Newcastle University, Newcastle, UK.

Introduction: Acute toxicity caused by New Psychoactive Substances (NPS) has created a significant burden for Emergency Departments (EDs). Here we report characteristics of people presenting with toxicity after exposure to the synthetic cathinone -ethylpentylone (NEP).

Methods: Adults presenting to hospital with severe acute toxicity after suspected NPS use were recruited between March 2015 and October 2020. Clinical features were recorded using consistent methodology and biological samples analysed using liquid chromatography-tandem mass-spectrometry.

Results: NEP was detected in at least one sample from 9 of 893 patients recruited during the period of study, all presenting between 2016 and 2019 and 8 presenting in southern England. Commonly reported clinical features included tachycardia (6), agitation (6), confusion (6), mydriasis (5), hallucinations (4), acidosis (3) and elevated creatine kinase (3). Co-used drugs, detected in 6 patients, may have contributed to these features, but agitation and hallucinations were also reported in all 3 patients without analytical evidence of co-use.

Conclusions: NEP was detected infrequently in episodes of drug toxicity in the UK between 2016 and 2019, especially in southern England. Clinical characteristics of toxicity are similar to those of other cathinones, although co-use of other drugs is common and may contribute to the features observed.
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http://dx.doi.org/10.1080/15563650.2021.1909730DOI Listing
April 2021

Variation of drugs involved in acute drug toxicity presentations based on age and sex: an epidemiological approach based on European emergency departments.

Clin Toxicol (Phila) 2021 Mar 16:1-13. Epub 2021 Mar 16.

Emergency Department, Hospital Clínic, IDIBAPS, Barcelona, Spain.

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;  < 0.001) and in all drug groups except benzodiazepines (median age 36 vs. 36 years;  = 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.
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http://dx.doi.org/10.1080/15563650.2021.1884693DOI Listing
March 2021

Rhabdomyolysis related to acute recreational drug toxicity-A Euro-DEN study.

PLoS One 2021 11;16(3):e0246297. Epub 2021 Mar 11.

Department of Clinical Toxicology, Medical University of Gdansk, Gdansk, Poland.

Background: This study was conducted to retrospectively assess the relationships between: rhabdomyolysis (quantified by creatine kinase (CK) activity) and kidney injury (quantified by serum creatinine concentration), sex, age, body temperature on admission, presence of seizures, and agitation or aggression in patients presenting to the Emergency Department with acute recreational drug toxicity. We also investigated the association with the substances ingested.

Methods: All presentations to the 16 sentinel Euro-DEN centres in 10 European countries with acute recreational drug toxicity during the first year of the Euro-DEN study (October 2013 to September 2014) were considered. Cases that had abnormal CK activity recorded as part of routine clinical care were divided into 3 cohorts depending on peak CK activity. Cases with normal CK activity were included as a control group (4th cohort).

Results: Only 1,015 (18.4%) of the 5,529 Euro-DEN presentations had CK activity concentration recorded. Of this group 353 (34.8%) had also creatinine concentration measured. There were 375 (36.9%) with minor rhabdomyolysis, 69 (6.8%) with moderate rhabdomyolysis, and 24 (2.4%) with severe rhabdomyolysis; 547 (53.9%) were included in the control group. There was a positive correlation between CK activity and creatinine concentration (correlation coefficient r = 0.71, p<0.0001). There was no correlation between CK activity and body temperature at the time of presentation to the ED (correlation coefficient r = 0.07, p = 0.03). There was a positive correlation between CK activity and length of stay in the hospital (r = 0.31, p<0.001). There was no association between CK activity and the presence of seizures (p = 0.33) or agitation/aggression (p = 0.45), patients age (p = 0.4) or sex (p = 0.25). The 5 most common agents amongst patients presenting with rhabdomyolysis were: cocaine (n = 107; 22.9% presentations), amphetamine (76; 16.2%), cannabis (74; 15.8%), GHB/GBL (72; 15.4%) and heroin (67; 14.3%). The distribution of rhabdomyolysis in 5 most common drugs was (drug; patients with rhabdomyolysis, patients without rhabdomyolysis): cocaine (107, 122), cannabis (74, 117), GHB/GBL (72, 81), amphetamine (76, 66), heroin (67, 70).

Conclusions: Abnormal values of CK activity occurred in almost half (46.1%) of presentations to the Emergency Department with acute recreational drug toxicity in whom CK activity was measured; however, severe rhabdomyolysis is seen in only a small minority (2.4%). Those with rhabdomyolysis are at significantly higher risk of kidney injury and have a longer length of hospital stay.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246297PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951866PMC
March 2021

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

Br J Clin Pharmacol 2021 04 2;87(4):1637-1646. Epub 2020 Nov 2.

Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London, 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.
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http://dx.doi.org/10.1111/bcp.14603DOI Listing
April 2021

Pharmacokinetics of Mephedrone Enantiomers in Whole Blood after a Controlled Intranasal Administration to Healthy Human Volunteers.

Pharmaceuticals (Basel) 2020 Dec 23;14(1). Epub 2020 Dec 23.

King's Forensics, Department of Analytical, Environmental and Forensic Sciences, King's College London, London SE1 9NH, UK.

Mephedrone, which is one of the most popular synthetic cathinones, has one chiral centre and thus exists as two enantiomers: -(+)-mephedrone and -(-)-mephedrone. There are some preliminary data suggesting that the enantiomers of mephedrone may display enantioselective pharmacokinetics and exhibit different neurological effects. In this study, enantiomers of mephedrone were resolved via chromatographic chiral recognition and the absolute configuration was unambiguously determined by a combination of elution order and chiroptical analysis (i.e., circular dichroism). A chiral liquid chromatography tandem mass spectrometry method was fully validated and was applied to the analysis of whole blood samples collected from a controlled intranasal administration of racemic mephedrone hydrochloride to healthy male volunteers. Both enantiomers showed similar kinetics, however, -(+)-mephedrone had a greater mean C of 48.5 ± 11.9 ng/mL and a longer mean half-life of 1.92 ± 0.27 h compared with 44.6 ± 11.8 ng/mL and 1.63 ± 0.23 h for -(-)-mephedrone, respectively. Moreover, -(+)-mephedrone had a lower mean clearance and roughly 1.3 times greater mean area under the curve than -(-)-mephedrone. Significant changes in the enantiomeric ratio over time were observed, which suggest that the analytes exhibit enantioselective pharmacokinetics. Even though the clinical significance of this finding is not yet fully understood, the study confirms that the chiral nature, and consequently the enantiomeric purity of mephedrone, can be a crucial consideration when interpreting toxicological results.
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http://dx.doi.org/10.3390/ph14010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822411PMC
December 2020

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

Br J Clin Pharmacol 2021 04 22;87(4):1660-1667. Epub 2020 Nov 22.

Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.

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.
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http://dx.doi.org/10.1111/bcp.14638DOI Listing
April 2021

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

Br J Clin Pharmacol 2021 04 5;87(4):1654-1659. Epub 2020 Nov 5.

Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.

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.
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http://dx.doi.org/10.1111/bcp.14592DOI Listing
April 2021

Pharmacokinetics of Mephedrone and Its Metabolites in Whole Blood and Plasma after Controlled Intranasal Administration to Healthy Human Volunteers.

J Anal Toxicol 2020 Sep 27. Epub 2020 Sep 27.

King's Forensics, Department of Analytical, Environmental and Forensic Sciences, King's College London, London, UK.

Mephedrone is a popular synthetic cathinone, known for its psychostimulant effects. At present, there is no data available on the pharmacokinetics of mephedrone and its metabolites in concurrently collected whole blood and plasma samples after a controlled intranasal administration to healthy volunteers. In this study, six healthy male volunteers nasally insufflated 100 mg of pure mephedrone hydrochloride (Day 1). Whole blood and plasma samples were collected at different timepoints after the administration and were analysed for the presence of mephedrone and its metabolites, dihydro-mephedrone (DHM), nor-mephedrone (NOR), hydroxytolyl-mephedrone (HYDROXY), 4-carboxy-mephedrone (4-CARBOXY) and dihydro-nor-mephedrone (DHNM), by validated liquid chromatography-tandem mass spectrometry methods. All analytes were detected in whole blood and plasma for 6 h post administration, with mephedrone and NOR also being detectable on Day 2 in some participants. 4-CARBOXY, followed by NOR, were the most abundant metabolites in both matrices. Compared to other psychostimulants, mephedrone showed rapid absorption (mean Tmax of 52.5 ± 20.7 min in plasma and 55.0 ± 18.2 min in whole blood) and elimination (mean t1/2 of 1.98 ± 0.30 h in plasma and 2.12 ± 0.33 h in whole blood). In addition, statistical analysis showed that median whole blood to plasma distribution ratios, reported here for the first time, were statistically different from 1 (unity) for mephedrone (median: 1.11), DHM (median: 1.30) and NOR (median: 0.765). It is hoped that the study will aid forensic and clinical toxicologists in detection, identification and interpretation of cases associated with mephedrone use.
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http://dx.doi.org/10.1093/jat/bkaa134DOI Listing
September 2020

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

Br J Clin Pharmacol 2021 04 15;87(4):1684-1694. Epub 2020 Sep 15.

Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

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.
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http://dx.doi.org/10.1111/bcp.14537DOI Listing
April 2021

Comparative Untargeted Metabolomics Analysis of the Psychostimulants 3,4-Methylenedioxy-Methamphetamine (MDMA), Amphetamine, and the Novel Psychoactive Substance Mephedrone after Controlled Drug Administration to Humans.

Metabolites 2020 Jul 27;10(8). Epub 2020 Jul 27.

Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, 8057 Zurich, Switzerland.

Psychoactive stimulants are a popular drug class which are used recreationally. Over the last decade, large numbers of new psychoactive substances (NPS) have entered the drug market and these pose a worldwide problem to human health. Metabolomics approaches are useful tools for simultaneous detection of endogenous metabolites affected by drug use. They allow identification of pathways or characteristic metabolites, which might support the understanding of pharmacological actions or act as indirect biomarkers of consumption behavior or analytical detectability. Herein, we performed a comparative metabolic profiling of three psychoactive stimulant drugs 3,4-methylenedioxymethamphetamine (MDMA), amphetamine and the NPS mephedrone by liquid chromatography-high resolution mass spectrometry (LC-HRMS) in order to identify common pathways or compounds. Plasma samples were obtained from controlled administration studies to humans. Various metabolites were identified as increased or decreased based on drug intake, mainly belonging to energy metabolism, steroid biosynthesis and amino acids. Linoleic acid and pregnenolone-sulfate changed similarly in response to intake of all drugs. Overall, mephedrone produced a profile more similar to that of amphetamine than MDMA in terms of affected energy metabolism. These data can provide the basis for further in-depth targeted metabolome studies on pharmacological actions and search for biomarkers of drug use.
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http://dx.doi.org/10.3390/metabo10080306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465486PMC
July 2020

MDMA-related presentations to the emergency departments of the European Drug Emergencies Network plus (Euro-DEN Plus) over the four-year period 2014-2017.

Clin Toxicol (Phila) 2021 Feb 17;59(2):131-137. Epub 2020 Jul 17.

Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland.

Context: 3,4-Methylenedioxymethamphetamine (MDMA) remains one of the most commonly used recreational drugs in Europe. Monitoring of Emergency Department (ED) presentations with acute toxicity associated with MDMA is important to determine trends in MDMA use and harms.

Methods: Data were extracted from the European Drug Emergencies Network (Euro-DEN) Plus database for all ED presentations with acute toxicity involving MDMA use, alone or in combination with other substances, between 1 January 2014 and 31 December 2017. Geographical distribution, time trends, patient demographics, clinical features, management and outcome were analysed.

Results: Out of 23,947 presentations, 2013 (8.4%) involved MDMA, used alone (88, 4.4%) or with other substances (1925, 95.6%). The proportion of MDMA presentations varied by country, from over 15% in France to less than 5% in Norway. For the 15 sentinel centres where data were available for all four years, MDMA-related presentations peaked in 2016 (10.4% 8.1% in 2015,  < 0.0001), thereafter decreasing in 2017 (8.2%,  = 0.0002). 1436 (71.3%) presentations involved males. Females were significantly younger than males (median 23 years, interquartile range, IQR, 20-27 years, median 25 years, IQR 21-30 years,  < 0.0001). Compared to presentations of acute toxicity with lone-use cocaine, presentations with lone-use MDMA occurred more frequently during the weekend (58.0% 43.9%,  = 0.02), were more frequently medically discharged directly from the ED (74.7% 62.4%,  = 0.03), and less frequently received sedation (43.5% 66.5%,  = 0.003).

Conclusions: This large multicentre series of MDMA presentations to EDs showed geographical variation and changes in time trends and in patient demographics. Triangulation with data from complementary sources including seizures, prevalence of use and wastewater analysis, will enable a greater understanding of the public health implications of MDMA use in Europe.
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http://dx.doi.org/10.1080/15563650.2020.1784914DOI Listing
February 2021

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

Br J Clin Pharmacol 2021 04 15;87(4):1668-1675. Epub 2020 Jul 15.

Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.

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.
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http://dx.doi.org/10.1111/bcp.14408DOI Listing
April 2021

Assessing the effect of extracorporeal treatments for lithium poisoning.

Br J Clin Pharmacol 2021 01 5;87(1):214-215. Epub 2020 Jun 5.

Departments of Clinical Pharmacology, Toxicology and Renal Medicine, St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia.

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http://dx.doi.org/10.1111/bcp.14367DOI Listing
January 2021

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

Br J Clin Pharmacol 2021 04 21;87(4):1676-1683. Epub 2020 Jun 21.

Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London, 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.
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http://dx.doi.org/10.1111/bcp.14397DOI Listing
April 2021

The challenge of the novel psychoactive substances: How have we responded and what are the implications of this response?

Br J Clin Pharmacol 2020 03 6;86(3):407-409. Epub 2020 Mar 6.

Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.

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http://dx.doi.org/10.1111/bcp.14236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080627PMC
March 2020

Detection of mephedrone and its metabolites in fingerprints from a controlled human administration study by liquid chromatography-tandem mass spectrometry and paper spray-mass spectrometry.

Analyst 2020 Apr 5;145(8):3038-3048. Epub 2020 Mar 5.

King's Forensics, Department of Analytical, Environmental and Forensic Sciences, King's College London, London, UK.

The use of synthetic stimulants, including designer cathinones, remains a significant concern worldwide. Thus, the detection and identification of synthetic cathinones in biological matrices is of paramount importance for clinical and forensic laboratories. In this study, distribution of mephedrone and its metabolites was investigated in fingerprints. Following a controlled human mephedrone administration (100 mg nasally insufflated), two mass spectrometry-based methods for fingerprint analysis have been evaluated. The samples deposited on triangular pieces of chromatography paper were directly analysed under ambient conditions by paper spray-mass spectrometry (PS-MS) while those deposited on glass cover slips were extracted and analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LC-MS/MS method was 5-6 times more sensitive than PS-MS but required sample preparation and longer analysis time. Mephedrone was detected in 62% and in 38% of all post-administration samples analysed by LC-MS/MS and PS-MS, respectively. Nor-mephedrone was the only metabolite detected in 3.8% of all samples analysed by LC-MS/MS. A large inter- and intra-subject variation was observed for mephedrone which may be due to several factors, such as the applied finger pressure, angle and duration of contact with the deposition surface and inability to control the 'amount' of collected fingerprint deposits. Until these limitations are addressed, we suggest that the sole use of fingerprints can be a useful diagnostic tool in qualitative rather than quantitative analysis, and requires a confirmatory analysis in a different biological matrix.
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http://dx.doi.org/10.1039/c9an02477hDOI Listing
April 2020

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

Invest Radiol 2020 07;55(7):405-411

Viapath Analytics, King's College Hospital NHS Foundation Trust, London, United Kingdom.

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.
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http://dx.doi.org/10.1097/RLI.0000000000000657DOI Listing
July 2020

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

Br J Clin Pharmacol 2020 03 4;86(3):517-527. Epub 2020 Mar 4.

Department of Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, 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.
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http://dx.doi.org/10.1111/bcp.14239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080623PMC
March 2020

Response to the letter from Wong

EClinicalMedicine 2019 Sep 27;14:13. Epub 2019 Sep 27.

Medical Toxicology Centre, Institute of Cellular Medicine, Newcastle University, Newcastle NE2 4HH, UK.

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http://dx.doi.org/10.1016/j.eclinm.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833363PMC
September 2019

Gadolinium-based contrast agents - what is the evidence for 'gadolinium deposition disease' and the use of chelation therapy?

Clin Toxicol (Phila) 2020 03 30;58(3):151-160. Epub 2019 Oct 30.

General Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Gadolinium-based contrast agents are widely used for magnetic resonance imaging and, until recently, had been generally considered to have an excellent safety profile in patients with normal renal function. Nephrogenic systemic fibrosis is a well-established disease process involving fibrosis of the skin and internal organs seen in some patients with severely impaired renal function following exposure to these agents. Following reports that individuals with normal renal function may experience gadolinium deposition within brain and bone tissue, the term "gadolinium deposition disease" has been proposed and the use of chelating agents has been recommended to treat this "disease". This review will address the clinical evidence for "gadolinium deposition disease" and discuss whether chelation therapy is appropriate for individuals who believe they have this condition. Electronic databases (PUBMED, Ovid MEDLINE and EMBASE) were searched up to 1 October 2019 for all studies evaluating clinical signs or symptoms related to potential gadolinium toxicity post-gadolinium-based contrast agent exposure in subjects with normal renal function, or papers evaluating the potential chelation of gadolinium in humans. We identified four clinical studies relating to "gadolinium deposition disease", including one that included some discussion of the use of chelation therapy. Two of the clinical studies presented data from anonymous online surveys that recruited participants from support forums for people who self-identified as having gadolinium-based contrast agent-induced toxicity, with questions focussing on their reported symptoms and signs. The published literature to date has demonstrated that gadolinium deposition within the brain primarily occurs within the dentate nucleus and globus pallidus. These patients did not complain of movement disorders, but instead reported generalised sensory symptoms, which would not be expected to occur with pathology in these areas of the brain. There was considerable selection bias and a lack of available clinical information to exclude alternative medical diagnoses for these series, thus rendering the results difficult to interpret. One study reported data from 25 patients who were diagnosed with "gadolinium deposition disease" according to unspecified criteria and were treated with intravenous calcium or zinc trisodium pentetate. The authors reported an increase in urine gadolinium concentrations following administration of the chelating agents, which they attributed to re-chelation of gadolinium from tissue deposits, however, there are insufficient data to be able to substantiate this. There is currently no published information from well-designed clinical studies that support a link between gadolinium deposition and the development of clinical sequelae in patients with normal renal function. Clinicians should exercise caution when considering whether or not gadolinium is of relevance in patients reporting symptoms after administration of gadolinium-based contrast agents. The inappropriate use of chelation therapy in patients with no clear evidence-based indication for their use potentially increases the risk of clinically significant harm to these patients from the adverse effects of chelation. Further research and well-designed clinical and epidemiological surveillance is needed to determine whether there are toxicological risks related to gadolinium exposure from the use of gadolinium-based contrast agents in patients with normal renal function.
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http://dx.doi.org/10.1080/15563650.2019.1681442DOI Listing
March 2020

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

Subst Use Misuse 2020 20;55(1):56-65. Epub 2019 Aug 20.

Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

There are reports of prescription stimulants being purchased online for use as cognitive enhancers or "smart drugs." 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. 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. 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. 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.
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http://dx.doi.org/10.1080/10826084.2019.1654516DOI Listing
October 2020

Consensus statements on the approach to patients in a methanol poisoning outbreak.

Clin Toxicol (Phila) 2019 12 22;57(12):1129-1136. Epub 2019 Jul 22.

The Norwegian CBRNE Centre of Medicine, Department of Acute Medicine, Oslo University Hospital, Oslo, Norway.

Methanol poisoning is an important cause of mortality and morbidity worldwide. Although it often occurs as smaller sporadic events, epidemic outbreaks are not uncommon due to the illicit manufacture and sale of alcoholic beverages. We aimed to define methanol poisoning outbreak (MPO), outline an approach to triaging an MPO, and define criteria for prioritizing antidotes, extracorporeal elimination treatments (i.e., dialysis), and indications for transferring patients in the context of an MPO. We convened a group of experts from across the world to explore geographical, socio-cultural and clinical considerations in the management of an MPO. The experts answered specific open-ended questions based on themes aligned to the goals of this project. This project used a modified Delphi process. The discussion continued until there was condensation of themes. We defined MPO as a sudden increase in the number of cases of methanol poisoning during a short period of time above what is normally expected in the population in that specific geographic area. Prompt initiation of an antidote is necessary in MPOs. Scarce hemodialysis resources require triage to identify patients most likely to benefit from this treatment. The sickest patients should not be transferred unless the time for transfer is very short. Transporting extracorporeal treatment equipment and antidotes may be more efficient. We have developed consensus statements on the response to a methanol poisoning outbreak. These can be used in any country and will be most effective when they are discussed by health authorities and clinicians prior to an outbreak.
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http://dx.doi.org/10.1080/15563650.2019.1636992DOI Listing
December 2019

Safety and Efficacy of the SNAP 12-hour Acetylcysteine Regimen for the Treatment of Paracetamol Overdose.

EClinicalMedicine 2019 May-Jun;11:11-17. Epub 2019 May 2.

Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, UK.

Background: Acetylcysteine (NAC) is effective at preventing liver injury after paracetamol overdose. The Scottish and Newcastle Anti-emetic Pre-treatment for Paracetamol Poisoning (SNAP) Study demonstrated that a 12 h NAC regimen was associated with fewer adverse drug reactions compared with the standard 21 h regimen. Here, we describe the clinical effectiveness of the SNAP NAC regimen.

Methods: The SNAP regimen, consisting of intravenous NAC 100 mg/kg over 2 h then 200 mg/kg over 10 h, was introduced to treat all paracetamol overdose patients at the Royal Infirmary of Edinburgh, the Royal Victoria Infirmary, Newcastle and St Thomas' Hospital, London. Patient data were prospectively and systematically collected before and after the change in treatment (total patients N = 3340, 21 h N = 1488, SNAP N = 1852). Health record linkage was used to determine patient outcome after hospital discharge.

Findings: There was no difference in liver injury or liver synthetic dysfunction between regimens. Hepatotoxicity (peak ALT > 1000 U/L) occurred in 64 (4.3%) and 67 (3.6%) patients, respectively, in the 21 h and SNAP groups (absolute difference - 0.7%, 95% CI - 2.1 to 0.6). Multivariable logistic regression did not identify treatment regimen as an outcome-associated factor. No patients were readmitted to hospital with, or died from, liver failure within 30 days of discharge. Anti-histamine treatment (for NAC anaphylactoid drug reactions) was prescribed for 163 (11.0%) patients with the 21 h regimen and 37 (2.0%) patients with the SNAP regimen (absolute difference 9.0% (95% CI 7.3 to 10.7)).

Interpretation: In clinical use the SNAP regimen has similar efficacy as standard therapy for preventing liver injury and produces fewer adverse reactions.
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http://dx.doi.org/10.1016/j.eclinm.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610779PMC
May 2019

Clinical relevance of ethanol coingestion in patients with GHB/GBL intoxication.

Toxicol Lett 2019 Oct 10;314:37-42. Epub 2019 Jul 10.

Emergency Department, Hospital Clínic, Barcelona, IDIBAPS, Barcelona, Spain; Medical School, University of Barcelona, Spain.

Objective: Ethanol intake can increase the sedative effects of gamma-hydroxybutyrate/gamma-butyrolactone (GHB/GBL), although the real clinical impact is unknown. We studied the clinical impact of the co-ingestion of ethanol in patients presenting to the Emergency Department (ED) with acute toxicity related to GHB/GBL use.

Method: We performed a secondary analysis of the Euro-DEN Plus Registry (14 countries, 22 EDs) which includes 17,371 consecutive patients presenting to the ED with acute recreational drug toxicity over 39 consecutive months (October 2013 - December 2016). We compared the epidemiological and clinical characteristics and ED management of patients identified as presenting with acute toxicity related to lone GHB/GBL (Group A) or GHB/GBL combined with ethanol (Group B) without other concomitant drugs.

Results: A total of 609 patients were included (age 32 (8) years; 116 women (19%); Group A: 183 patients and Group B: 426). The most common features were reduction in consciousness (defined as Glasgow Coma Score <13 points: 56.1%) and agitation/aggressiveness (33.6%). Those with ethanol co-ingestion were younger patients (Group A/B: 31.5/33.1 years, p = 0.029) and ethanol co-ingestion was associated with a lower frequency of bradycardia (23.5%/15.7%, p = 0.027) and more frequent arrival at the ED by ambulance (68.3/86.6%; p < 0.001), reduction in consciousness (58.9%/49.1%; p = 0.031), need for treatment in the ED (49.2%/60.4%; p = 0.011), use of sedatives (20.1%/12.8%; p = 0.034), admission to critical care units (22.4%/55.3%; p < 0.001), and longer hospital stay (stay longer than 6 h: 16.9%/28.4%; p = 0.003).

Conclusions: Co-ingestion of ethanol increases the adverse effects of patients intoxicated by GHB/GBL, leading to greater depression of consciousness, need for treatment, admission to the ICU and longer hospital stay.
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http://dx.doi.org/10.1016/j.toxlet.2019.07.001DOI Listing
October 2019

Nonmedical use of alprazolam in the UK: Results from a nationally representative survey.

Br J Clin Pharmacol 2019 08 5;85(8):1841-1845. Epub 2019 Jun 5.

Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London, SE1 7EH, UK.

There is concern in the UK about nonmedical use (NMU) of alprazolam (Xanax). We investigated the epidemiology of alprazolam NMU compared with diazepam using data from the Survey of Non-Medical Use of Prescription Drugs (NMURx) programme (collected 28 September-1 December 2017). The survey included 10 019 respondents and was weighted by age, sex and region to represent 52 927 659 UK adults. The estimated national prevalence of lifetime NMU of alprazolam was 0.32% (95% confidence interval: 0.19-0.46), and 1.30% (1.06-1.54) for diazepam. The prevalence of NMU in the last 90 days was significantly different when split by age category for alprazolam (P < .001), but not for diazepam (P = .262) with alprazolam NMU being more common among younger adults (age 16-24 years: 0.37%; age 25-34 years: 0.14%; 35 years or older: 0.01%). Further research is needed to fully understand the motivations of alprazolam NMU and to monitor whether the popularity of alprazolam will rise.
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http://dx.doi.org/10.1111/bcp.13959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624393PMC
August 2019

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

Drug Test Anal 2019 Sep 25;11(9):1419-1430. Epub 2019 Jul 25.

Analytical and Environmental Sciences Research Division, Faculty of Life Sciences and Medicine, King's College London, UK.

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 C of COC and its major metabolites, benzoylecgonine (BZE) and ecgonine methyl ester (EME), were closely related in whole blood and plasma. The median C 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 C 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 (R  = 0.0914 R = 0.956, p < 0.0001), as was BZE (R  = 0.0932 R = 0.965, p < 0.0001) and EME (R  = 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.
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http://dx.doi.org/10.1002/dta.2657DOI Listing
September 2019
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