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Introduction: Popular "pod-style" e-cigarettes commonly use nicotine salt-based e-liquids that cause less irritation when inhaled and can deliver higher nicotine concentrations than free-base nicotine. This study investigated the pharmacokinetic and pharmacodynamic effects of different nicotine formulations (salt vs. free-base) and concentrations that might influence systemic nicotine absorption and appeal of e-cigarettes., Aims and Methods: In this randomized, double-blind, within-subject crossover study, 20 non-nicotine-naïve participants were switched among three e-liquids (free-base nicotine 20 mg/mL, nicotine salt 20 mg/mL, nicotine salt 40 mg/mL) using a refillable pod system and a standardized vaping protocol (one puff every 30 seconds, 10 puffs total). Serum nicotine concentrations and vital signs were assessed over 180 minutes; direct effects, craving, satisfaction, withdrawal, and respiratory symptoms were measured using questionnaires. CYP2A6 genotypes and the nicotine metabolite ratio were also assessed., Results: Eleven (55%) participants were male and the median age was 23.5 years (range 18-67). All three formulations differed significantly in peak serum nicotine concentration (baseline adjusted Cmax, median (range): 12.0 ng/mL (1.6-27.3), 5.4 ng/mL (1.9-18.7), and 3.0 ng/mL (1.3-8.8) for nicotine salt 40 mg/mL, nicotine salt 20 mg/mL and free-base 20 mg/mL, respectively). All groups reached Cmax 2.0-2.5 minutes (median) after their last puff. Differences in subjective effects were not statistically significant. No serious adverse events were observed., Conclusions: Free-base 20 mg/mL formulations achieved lower blood nicotine concentrations than nicotine salt 20 mg/mL, while 40 mg/mL nicotine salt yielded concentrations similar to cigarette smoking. The findings can inform regulatory policy regarding e-liquids and their potential use in smoking cessation., Implications: Nicotine salt formulations inhaled by an e-cigarette led to higher nicotine delivery compared to nicotine-free-base formulations with the same nicotine concentration. These findings should be considered in future regulatory discussions. The 40 mg/mL nicotine salt formulation showed similar nicotine delivery as combustible cigarettes, albeit at concentrations over the maximum limit for e-liquids allowed in the European Union. Nicotine delivery resembling combustible cigarettes might be beneficial for smokers willing to quit to adequately alleviate withdrawal symptoms. However, increased nicotine delivery can also pose a public health risk, raising concerns about abuse liability, especially among youth and nonsmokers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Bleeding events are common in patients prescribed anticoagulants and can have devastating consequences. Several specific and nonspecific agents have been developed to reverse the effects of anticoagulant drugs or toxins. Vitamin K, as the oldest of these antidotes, specifically counteracts the effects of pharmaceuticals and rodenticides designed to deplete stores of vitamin K-dependent factors. In cases of life-threatening bleeding, the addition of prothrombin complex concentrates (PCCs) allows for the immediate replacement of coagulation factors. While the use of PCCs has been extended to the non-specific reversal of the effects of newer direct oral anticoagulants, the specific agents idarucizumab, targeting dabigatran and andexanet-α, binding factor Xa inhibitors, have recently been developed and are being preferentially recommended by most guidelines. However, despite having rapid effects on correcting coagulopathy, there is to date a lack of robust evidence establishing the clear superiority of direct oral anticoagulant-specific reversal agents over PCCs in terms of haemostatic efficacy, safety or mortality. For andexanet-α, a potential signal of increased thromboembolic risks, comparatively high costs and low availability might also limit its use, even though emerging evidence appears to bolster its role in intracranial haemorrhage. Protamine is the specific agent for the reversal of unfractionated heparin anticoagulation used mainly in cardiovascular surgery. It is much less effective for low molecular weight heparin fragments and is usually reserved for cases with life-threatening bleeding., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: In case of suspected acute recreational drug toxicity, immunoassays are commonly used as diagnostic tools. Although easy to handle, understanding of their limitations is necessary for a correct interpretation of the results. The aim of this project was to investigate residents' knowledge regarding drug screening immunoassays at a Swiss hospital group., Methods: All residents of a large hospital group in Switzerland were invited by e-mail to participate in an anonymous survey. Following ten multiple choice questions on drug screening tests, the participants were also asked about their demographics, whether they used drug screening tests on a regular basis, and how confident they felt in their ability to interpret test results., Results: The ten knowledge questions were answered by 110 of the 1026 residents (11%). Among the 108 participants with available demographics, 90% were 25-35 years old, 63% were female, and 70% were at least in their 4 th year of residency. The median score of correct answers was 4 out of 10 (range 0-7) and in 50% of the questions, the correct answer was the most frequently selected response. No significant differences in the knowledge scores were found based on the training, confidence level, or the frequency of drug tests used in daily work., Conclusion: This survey revealed widespread knowledge gaps among residents regarding the interpretation of immunoassay-based drug test results. These findings can be used to implement educational measures on this topic and might provide a basis for targeted information on common pitfalls to be included in laboratory reports., Competing Interests: The authors declare that they have no conflicts of interest in relation to this work., (Copyright © 2024 Elias Bekka et al.)

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

Background: Self-discharge is a risk factor for readmission and excess mortality. We assess the rate of self-discharge from the emergency department (ED) among presentations for acute recreational drug toxicity and identify factors associated with self-discharge., Methods: From the Euro-DEN Plus database of presentations to the ED with acute recreational drug toxicity, we extracted data from 11 centres in seven European countries from 2014 to 2017. Self-discharge was defined as taking one's own discharge or escaping from the ED before being medically cleared. We used multiple logistic regression analyses to look for factors associated with self-discharge., Results: Among 15,135 included presentations, 1807 (11.9%) self-discharged. Self-discharge rates varied from 1.7 to 17.1% between centres. Synthetic cannabinoids were associated with self-discharge, adjusted odds ratio 1.44 (95% confidence interval 1.10-1.89), as were heroin, 1.44 (1.26-1.64), agitation, 1.27 (1.10-1.46), and naloxone treatment, 1.27 (1.07-1.51), while sedation protected from self-discharge, 0.38 (0.30-0.48)., Conclusion: One in eight presentations self-discharged. There was a large variation in self-discharge rates across the participating centres, possibly partly reflecting different discharge procedures and practices. Measures to improve the management of agitation and cautious administration of naloxone to avoid opioid withdrawal symptoms may be approaches worth exploring to reduce self-discharge., (© 2023. The Author(s).)

Objective: Presentations of Taxus baccata (yew) poisoning can range between asymptomatic cases and life-threatening cardiotoxicity - depending on the amount ingested. This study aimed to describe emergency department (ED) presentations after yew exposure, and covers their clinical presentation, diagnostic and specific treatment, to contribute to optimising intreatment and prophylaxis., Methods: Retrospective observational study of cases (≥ 16 years of age) presenting at the ED of the University Hospital of Bern, Switzerland, from 1 May 2012 to 31 May 2020 following reported yew exposure. Cases were retrieved from the electronic patient database using full-text terms., Results: During the study period, 55 presentations (11 patients) of the 350,381 ED attendances were included. All patients were female and the median age on first presentation was 22 years (range 16-48). All 10 patients with intentional intake had previous diagnoses of psychiatric disorders. Commonly reported symptoms on presentation were gastrointestinal disturbances (31 presentations, 56%), neurological (six presentations, 11%) and subjective cardiovascular symptoms (five presentations, 9%). The most frequent clinical findings on presentation were tachycardia (15 presentations, 27%) and hypotension (11 presentations, 20%). In 52 presentations (95%), gastroscopic extraction of the leaves was performed, activated charcoal was administered in 25 cases (45%), and there were no fatalities. In the majority of the cases (40, 73%), the patient was admitted to psychiatric care and in 10 (18%) the patient was discharged home., Conclusion: ED presentations after yew exposure appear to be rare, but potentially life-threatening and commonly observed in this study in young female patients with underlying psychiatric diseases. In this case series, gastroscopic extraction and activated charcoal application were commonly performed and there were no fatalities.

This narrative review examines the impact of cigarette smoking and the use of other tobacco and nicotine products on cardiovascular disease. Smoking increases the incidence of both acute and chronic cardiovascular diseases, and the harmful effects are substantially and relatively quickly reversible after quitting. Recommended cessation treatment includes offering pharmacotherapy, counseling which should emphasize the rapid risk reduction that occurs after quitting and adequate follow-up contacts. Although most research on cardiovascular disease in relation to tobacco use has focused upon cigarette smoking, we also review available data related to other combustible tobacco products, smokeless tobacco, electronic nicotine delivery systems and second-hand smoke. We discuss the implications of smoking on clinical management of patients with heart disease and newer developments with potential relevance to treatment of such patients., (© 2021 Society for the Study of Addiction.)

Aims of the Study: The stimulant methamphetamine (e.g., "crystal meth") is a commonly abused drug in many parts of the world and can cause significant health problems. The present study aims to describe presentations with reported methamphetamine use at an urban emergency department (ED) in Switzerland, to investigate prevalence, patterns and susceptible groups., Methods: Retrospective study at the ED of the University Hospital of Bern, Switzerland. Cases from June 2012 to July 2019 were retrieved from the electronic patient database using full-text terms and were categorised into three groups based on patient history: "acute", if patients presented within 72 hours of last reported use, "chronic" in cases of regular use but not within the previous 72 hours, and "past" in cases of discontinued consumption. Cases with a positive methamphetamine urine drug screening test with no further information available were described separately., Results: During the study period, 40 cases were categorised as "acute". Among those, the mean age was 29.5 years (standard deviation [SD] 8.7), 75% (n = 30) were male, and agitation (n = 11, 28%), hypertension (n = 11, 28%), tachycardia (n = 11, 28%), sleep disturbances (n = 10, 25%) and aggression (n = 8, 20%) were the most common symptoms. Most patients (n = 22, 55%) were medically discharged, but 35% (n = 14) were admitted to a psychiatric clinic. Most (n = 33, 82.5%) were polydrug users, with alcohol, cocaine and cannabis being the most frequent co-used substances. The "chronic" group included 37 cases. Those patients were mostly male (n = 26, 70%), with a mean age of 31 years (SD 11.0), and 46% (n = 17) presented because of psychiatric symptoms, such as psychosis, depression or aggression. Of the 45 cases in the "past" group (mean age of 30 years, SD 8.6), 69% (n = 31) were male, and 49% (n = 22) and 24% (n = 11), respectively, had medical and psychiatric symptoms as the reason for admission. Of 61 cases with a positive urine drug screening test as the sole indicator of methamphetamine use, 19 patients reported MDMA use (cross-reactivity with methamphetamine in the urine immunoassay used). In the 42 remaining cases, it was unclear if the positive result was due to unreported methamphetamine use or cross-reactivity., Conclusions: Most patients with reported methamphetamine use were young and male, with signs of sympathomimetic arousal and/or psychiatric symptoms. Although ED visits with reports of methamphetamine use appear to be uncommon, consumption-related health problems can require significant pre- and in-hospital resources.

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

A relatively high proportion of attempted suicides employ self-poisoning with medication. Data from emergency department presentations can help to identify possible risk drug classes and provide a basis for preventive measures. This retrospective analysis included cases presenting at the emergency department of the University Hospital of Bern, Switzerland, from May 2012 to August 2016, after attempted suicide with drugs. We excluded attempted suicides with only alcohol or other non-medical substances. During the study period, there were 488 cases (466 patients) of attempted suicide with medical substances. The median patient age was 33 years (range 16-93) and 354 (73%) cases were female. The most commonly involved substances/drug classes were benzo-diazepines ( n = 167, 34%), neuroleptics ( n = 114, 23%) and paracetamol ( n = 111, 23%). A total of 231 (47%) cases employed only a single substance. Common symptoms included somnolence ( n = 245, 50%), tachycardia ( n = 119, 24%) and nausea/vomiting ( n = 76, 16%). In most cases, the poisoning was of minor severity ( n = 231, 47%) and the patients were admitted to a psychiatric hospital ( n = 264, 54%). Important preventive measures may include careful monitoring for suicidal behaviour when prescribing psychotropic drugs, in addition to restrictions in pack size. Efforts should also be made to enhance the awareness of health professionals qualified to prescribe or supply paracetamol.

Aim: The objective was to investigate the effect of metamizole on renal function in healthy, salt-depleted volunteers. In addition, the pharmacokinetics of the four major metamizole metabolites were assessed and correlated with the pharmacodynamic effect using urinary excretion of the prostacyclin metabolite 6-keto-prostaglandin F1α. Methods: Fifteen healthy male volunteers were studied in an open-label randomized controlled parallel group study. Eight subjects received oral metamizole 1,000 mg three times daily and seven subjects naproxen 500 mg twice daily for 7 days. All subjects were on a low sodium diet (50 mmol sodium/day) starting 1 week prior to dosing until the end of the study. Glomerular filtration rate was measured using inulin clearance. Urinary excretion of sodium, potassium, creatinine, 6-keto-prostaglandin F1α, and pharmacokinetic parameters of naproxen and metamizole metabolites were assessed after the first and after repeated dosing. Results: In moderately sodium-depleted healthy subjects, single or multiple dose metamizole or naproxen did not significantly affect inulin and creatinine clearance or sodium excretion. Both drugs reduced renal 6-keto-prostaglandin F1α excretion after single and repeated dosing. The effect started 2 h after intake, persisted for the entire dosing period and correlated with the concentration-profile of naproxen and the active metamizole metabolite 4-methylaminoantipyrine (4-MAA). PKPD modelling indicated less potent COX-inhibition by 4-MAA (EC 50 0.69 ± 0.27 µM) compared with naproxen (EC 50 0.034 ± 0.033 µM). Conclusions: Short term treatment with metamizole or naproxen has no significant effect on renal function in moderately sodium depleted healthy subjects. At clinically relevant doses, 4-MAA and naproxen both inhibit COX-mediated renal prostacyclin synthesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Blaser, Duthaler, Bouitbir, Leuppi-Taegtmeyer, Liakoni, Dolf, Mayr, Drewe, Krähenbühl and Haschke.)

Background: Statins are effective lipid-lowering drugs for the prevention of cardiovascular disease, but muscular adverse events can limit their use. Hydrophilic statins (pravastatin, rosuvastatin) may cause less muscular events than lipophilic statins (e.g. simvastatin, atorvastatin) due to lower passive diffusion into muscle cells., Objective: To compare the risk of muscular events between statins at comparable lipid-lowering doses and to evaluate if hydrophilic statins are associated with a lower muscular risk than lipophilic statins., Design/setting: Propensity score-matched cohort study using data from the United Kingdom-based Clinical Practice Research Datalink (CPRD) GOLD., Patients: New statin users. Cohort 1: pravastatin 20-40 mg (hydrophilic) vs simvastatin 10-20 mg (lipophilic), cohort 2: rosuvastatin 5-40 mg (hydrophilic) vs atorvastatin 10-80 mg (lipophilic), and cohort 3: simvastatin 40-80 mg vs atorvastatin 10-20 mg., Main Measures: The outcome was a first record of a muscular event (myopathy, myalgia, myositis, rhabdomyolysis) during a maximum follow-up of 1 year., Key Results: The propensity score-matched cohorts consisted of 1) 9,703, 2) 7,032, and 3) 37,743 pairs of statin users. Comparing the risk of muscular events between low-intensity pravastatin vs low-intensity simvastatin yielded a HR of 0.86 (95% CI 0.64-1.16). In the comparison of moderate- to high-intensity rosuvastatin vs equivalent doses of atorvastatin, we observed a HR of 1.17 (95% CI 0.88-1.56). Moderate- to high-intensity simvastatin was associated with a HR of 1.33 (95% CI 1.16-1.53), when compared with atorvastatin at equivalent doses., Limitations: We could not conduct other pairwise comparisons of statins due to small sample size. In the absence of a uniform definition on the comparability of statin doses, the applied dose ratios may not fully match with all literature sources., Conclusions: Our results do not suggest a systematically lower risk of muscular events for hydrophilic statins when compared to lipophilic statins at comparable lipid-lowering doses., (© 2021. The Author(s).)

Electronic nicotine delivery systems (ENDS) such as e-cigarettes and heated tobacco products are novel battery-operated devices that deliver nicotine without combustion of tobacco. Because cigarette smoking is sustained by nicotine addiction and the toxic combustion products are mainly responsible for the harmful effects of smoking, ENDS could be used to promote smoking cessation while exposing users to lower levels of toxicants compared with conventional cigarettes. The currently available evidence from clinical and observational studies indicates a potential role of e-cigarettes as smoking cessation aids, although many continue to use e-cigarettes long after quitting smoking. Nicotine and toxicant delivery vary considerably by device and depend on the characteristics of the e-liquid formulation. Because smokers tend to titrate their nicotine intake to maintain their desired pharmacologic effects, device and liquid characteristics need to be considered when using ENDS as an aid to quit smoking. Factors potentially limiting their use are the currently still unknown long-term safety of these products and concerns regarding widespread use among youth. Implications of clinical pharmacology data on ENDS for the cigarette endgame and regulation by the U.S. Food and Drug administration are discussed., (© 2021, The American College of Clinical Pharmacology.)

Objectives: To investigate if the nicotine metabolite ratio (NMR, the ratio of nicotine metabolites 3'-hydroxycotinine/cotinine) is a reliable phenotypic biomarker for nicotine clearance across races, and as a function of differences in the rate of nicotine, cotinine and 3'-hydroxycotinine glucuronidation and UGT genotypes., Methods: Participants [Caucasians (Whites), African Americans (Blacks) and Asian-Americans (Asians)] received an oral solution of deuterium-labeled nicotine and its metabolite cotinine. Plasma and saliva concentrations of nicotine and cotinine were used to determine oral clearances. Rates of glucuronidation were assessed from urine glucuronide/parent ratios, and UGT2B10 and UGT2B17 genotypes from DNA., Results: Among the 227 participants, 96 (42%) were White, 67 (30%) Asian and 64 (28%) Black. Compared to the other two races, Whites had higher nicotine and cotinine total oral clearance, Blacks had lower nicotine and cotinine glucuronidation rates and Asians had lower 3'-hydroxycotinine glucuronidation rates. A strong positive correlation (correlations coefficients 0.77-0.84; P < 0.001) between NMR and nicotine oral clearance was found for all three races, and NMR remained a strong predictor for the nicotine oral clearance while adjusting for race, sex and age. Neither the metabolite glucuronidation ratios nor the UGT genotypes had significant effects on the ability of NMR to predict nicotine oral clearance., Conclusion: NMR appears to be a reliable phenotypic biomarker for nicotine clearance across races, glucuronidation phenotypes and genotypes. Racial differences in the relationships between NMR, smoking behaviors and addiction are unlikely to be related to an inadequate estimation of nicotine clearance on the basis of NMR., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: To investigate the influence of a cytochrome P450 CYP3A4 and efflux transporter P-glycoprotein (P-gp) inducing Hypericum perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban., Methods: Open-label, nonrandomized, sequential treatment interaction study. Following CYP3A4 and P-gp phenotyping using low-dose midazolam and fexofenadine, 12 healthy volunteers received a single oral dose of 20 mg rivaroxaban and rivaroxaban plasma concentrations and inhibition of the activated coagulation factor X (factor Xa) activity were measured prior to and up to 48 h postdosing. The procedures were repeated after 2 weeks' treatment with the H. perforatum extract., Results: The geometric mean ratios for the area under the concentration-time curve and C max of rivaroxaban after/before induction with the H. perforatum extract were 0.76 (90% confidence interval [CI] 0.70, 0.82) and 0.86 (90% CI 0.76, 0.97), respectively. Inhibition of factor Xa activity was reduced with a geometric mean area under the effect-time curve ratio after/before induction of 0.80 (90% CI 0.71, 0.89). No clinically significant differences were found regarding T max (median 1.5 vs 1 h, P = .26) and terminal elimination half-life (mean 10.6 vs 10.8 h, P = .93) of rivaroxaban. The H. perforatum extract significantly induced CYP3A4 and P-gp activity, as evidenced by phenotyping., Conclusion: The CYP3A4/P-gp inducing H. perforatum extract caused a decrease of rivaroxaban exposure with a proportional decrease of the pharmacodynamic effect. Although the data do not justify a contraindication for the combination or a systematic adjustment of rivaroxaban dosage, avoidance of the combination or laboratory monitoring should be considered in patients taking hyperforin-containing H. perforatum extracts with rivaroxaban., (© 2020 British Pharmacological Society.)

Background: Clinical risk scores and machine learning models based on routine laboratory values could assist in automated early identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients at risk for severe clinical outcomes. They can guide patient triage, inform allocation of health care resources, and contribute to the improvement of clinical outcomes., Methods: In- and out-patients tested positive for SARS-CoV-2 at the Insel Hospital Group Bern, Switzerland, between February 1st and August 31st ('first wave', n = 198) and September 1st through November 16th 2020 ('second wave', n = 459) were used as training and prospective validation cohort, respectively. A clinical risk stratification score and machine learning (ML) models were developed using demographic data, medical history, and laboratory values taken up to 3 days before, or 1 day after, positive testing to predict severe outcomes of hospitalization (a composite endpoint of admission to intensive care, or death from any cause). Test accuracy was assessed using the area under the receiver operating characteristic curve (AUROC)., Results: Sex, C-reactive protein, sodium, hemoglobin, glomerular filtration rate, glucose, and leucocytes around the time of first positive testing (- 3 to + 1 days) were the most predictive parameters. AUROC of the risk stratification score on training data (AUROC = 0.94, positive predictive value (PPV) = 0.97, negative predictive value (NPV) = 0.80) were comparable to the prospective validation cohort (AUROC = 0.85, PPV = 0.91, NPV = 0.81). The most successful ML algorithm with respect to AUROC was support vector machines (median = 0.96, interquartile range = 0.85-0.99, PPV = 0.90, NPV = 0.58)., Conclusion: With a small set of easily obtainable parameters, both the clinical risk stratification score and the ML models were predictive for severe outcomes at our tertiary hospital center, and performed well in prospective validation.

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% versus 8.1% in 2015, p  < 0.0001), thereafter decreasing in 2017 (8.2%, p  = 0.0002). 1436 (71.3%) presentations involved males. Females were significantly younger than males (median 23 years, interquartile range, IQR, 20-27 years, versus median 25 years, IQR 21-30 years, p  < 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% versus 43.9%, p  = 0.02), were more frequently medically discharged directly from the ED (74.7% versus 62.4%, p  = 0.03), and less frequently received sedation (43.5% versus 66.5%, p  = 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.

Aims of the Study: Adverse drug reactions (ADRs) are an important cause of hospital admissions. Insufficient data are available about the frequency and characteristics of ADR-related emergency readmissions in Switzerland. The aim of this retrospective study was to characterise ADRs related to short-term emergency readmissions in a large Swiss University Hospital and to assess their reporting frequency., Methods: Electronic records of all patients discharged from the University Hospital Bern within a 12-month period (1 January to 31 December 2012) and emergency readmission within 30 calendar days were reviewed. Case inclusion required a known ADR. Cases with intentional overdosing, lack of compliance or insufficient documentation were excluded. Identified ADR-related readmission cases were searched in the Swiss ADR reporting system to assess reporting rate., Results: There were 1294 emergency readmissions among the 4792 readmissions (14% of all admissions) within 30 days after discharge. We identified 270 cases of ADR-related readmissions, corresponding to 21% of emergency readmissions and 6% of all readmissions within 30 days. The most frequent ADRs were gastrointestinal disorders (26%), infections and infestations (19%), and nervous system disorders (10%). The most frequent drug classes leading to ADRs were antineoplastic/immunomodulating (35%) and antithrombotic agents (25%). Only 8 (3%) of the 270 cases were reported to the Swiss ADR reporting system., Conclusion: ADR-related readmissions constituted a considerable part of short-term emergency readmissions. Despite being a relevant cause for rehospitalisation, only a minority of the ADRs were reported to the regulatory authorities. Strategies to prevent ADR-related readmissions and to improve reporting rates are needed.

Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations ( p < 1 × 10 -7 ) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41-6.68, p = 1.01 × 10 -7 ) and rs4427239 (OR = 5.47, 95%CI: 2.81-10.65, p = 5.75 × 10 -7 ), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.

Background and Objective: Agranulocytosis is a rare and potentially life-threatening complication of metamizole (dipyrone) intake that is characterized by a loss of circulating neutrophil granulocytes. While the mechanism underlying this adverse drug reaction is not well understood, involvement of the immune system has been suggested. In addition, associations between genetic variants in the Human Leukocyte Antigen (HLA) region and agranulocytosis induced by other drugs have been reported. The aim of the present study was to assess whether genetic variants in classical HLA genes are associated with the susceptibility to metamizole-induced agranulocytosis (MIA) in a European population by targeted resequencing of eight HLA genes. Design: A case-control cohort of Swiss patients with a history of neutropenia or agranulocytosis associated with metamizole exposure ( n = 53), metamizole-tolerant ( n = 39) and unexposed controls ( n = 161) was recruited for this study. A high-throughput resequencing (HTS) and high-resolution typing method was used to sequence and analyze eight HLA loci in a discovery subset of this cohort ( n = 31 cases, n = 38 controls). Identified candidate alleles were investigated in the full Swiss cohort as well as in two independent cohorts from Germany and Spain using HLA imputation from genome-wide SNP array data. In addition, variant calling based on HTS data was performed in the discovery subset for the class I genes HLA-A , - B , and - C using the HLA-specific mapper hla-mapper . Results: Eight candidate alleles ( p < 0.05) were identified in the discovery subset, of which HLA - C ∗ 04:01 was associated with MIA in the full Swiss cohort ( p < 0.01) restricted to agranulocytosis (ANC < 0.5 × 10 9 /L) cases. However, no candidate allele showed a consistent association in the Swiss, German and Spanish cohorts. Analysis of individual sequence variants in class I genes produced consistent results with HLA typing but did not reveal additional small nucleotide variants associated with MIA. Conclusion: Our results do not support an HLA-restricted T cell-mediated immune mechanism for MIA. However, we established an efficient high-resolution (three-field) eight-locus HTS HLA resequencing method to interrogate the HLA region and demonstrated the feasibility of its application to pharmacogenetic studies., (Copyright © 2020 Cismaru, Grimm, Rudin, Ibañez, Liakoni, Bonadies, Kreutz, Hallberg, Wadelius, EuDAC Collaborators, Haschke, Largiadèr and Amstutz.)

Introduction: The rate of nicotine metabolism, estimated by the nicotine metabolite ratio (NMR), is an important determinant of tobacco dependence. This study investigated the effect of NMR on smoking behavior due to nicotine reinforcement during ad libitum smoking., Aims and Methods: As part of a larger study, participants were stratified based on saliva NMR as fast and slow metabolizers. After smoking a cigarette and measuring nicotine blood concentrations, participants smoked as desired over a 90-minute period. Analysis included time to first cigarette, total number of cigarettes, total number of puffs, and weight of tobacco consumed., Results: Sixty-one (48%) participants were fast metabolizers and 66 (52%) slow metabolizers by NMR. No significant differences were found regarding the smoking topography variables by NMR. Normal metabolizers by genotype (n = 79) had a shorter time to first cigarette than reduced metabolizers (n = 39; p = .032). Blacks smoked fewer cigarettes (p = .008) and took fewer total puffs (p = .002) compared with Whites. Among Whites, fast metabolizers by NMR had a shorter time to first cigarette compared with slow metabolizers (p = .014). Among fast metabolizers, Whites had, compared with Blacks, shorter latency to first cigarette (p = .003) and higher number of total puffs (p = .014) and cigarettes smoked (p = .014). Baseline cigarettes per day and nicotine elimination half-life significantly predicted topography outcomes., Conclusions: Saliva NMR did not predict cigarette reinforcement during a relatively brief period of ad libitum smoking. Differences were seen by race, with White fast metabolizers by NMR having shorter time to first cigarettes compared with slow metabolizers., Implications: After a 90-minute period of nicotine abstinence, NMR was not significantly associated with smoking reinforcement. Slow and fast metabolizers had similar time to first cigarette, number of cigarettes smoked, total number of puffs, and tobacco consumed; however, within-race differences show that within Whites, fast metabolizers had a faster time to first cigarette than slow metabolizers., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

New psychoactive substances (NPS) have emerged worldwide in recent years, posing a threat to public health and a challenge to drug policy. NPS are usually derivatives or analogues of classical recreational drugs designed to imitate their effects while circumventing regulations. This article provides an overview of benefits and limitations of analytical screening in managing patients presenting with acute NPS toxicity. NPS typically cannot be analytically identified with the usual immunoassay tests. To detect NPS using an immunoassay, antibodies specifically binding to the new structures would have to be developed, which is complicated by the rapid change of the NPS market. Activity-based assays could circumvent this problem since no prior knowledge on the substance structure is necessary. However, classical recreational drugs activating the same receptors could lead to false positive results. Liquid or gas chromatography coupled with mass spectrometry is a valuable NPS analysis tool, but its costs (e.g. equipment), run time (results usually within hours vs minutes in case of immunoasssays) and the need for specialized personnel hinder its use in clinical setting, while factors such as lack of reference standards can pose further limitations. Although supportive measures are sufficient in most cases for adequate patient management, the detection and identification of NPS can contribute significantly to public health and safety in cases of e.g. cluster intoxications and outbreaks, and to the investigation of these novel compounds' properties. However, this requires not only availability of the necessary equipment and personnel, but also collaboration between clinicians, authorities and laboratories., (© 2019 The British Pharmacological Society.)

Comparisons of systemic exposure to toxicants during monitored cigarette smoking, electronic cigarette (e-cigarette) use, and abstention are needed to enhance our understanding of the risks of e-cigarette use (vaping). In a cross-over study, we measured 10 mercapturic acid metabolites of volatile organic compounds (VOCs) in 24-hour urine samples collected from 36 dual users (8 women) of e-cigarettes and cigarettes during 2 days of ad libitum vaping or cigarette-only use, and 2 days of enforced abstention. Concentrations of VOC metabolites were higher during smoking compared with vaping, except for the methylating agents' metabolite. The fold-difference in concentrations when smoking relative to vaping ranged from 1.31 (1.06-1.61; geometric mean, 95% confidence interval; 1,3-butadiene) to 7.09 (5.88-8.54; acrylonitrile). Metabolites of acrylamide [fold difference of 1.21 (1.03-1.43)] and benzene [1.46 (1.13-1.90)] were higher during vaping compared with abstention. The 1,3-butadiene and propylene oxide metabolites were higher in variable-power tank users compared with users of cig-a-likes. E-cigarettes expose users to lower levels of toxic VOCs compared with cigarette smoking, supporting their harm reduction potential among smokers. However, some e-cigarettes expose users to VOCs such as acrylamide, benzene, and propylene oxide, and may pose health risks to nonsmoking users. The results of our study will inform regulators in assessing e-cigarettes with respect to the balance between its potential harm reduction for adult smokers and risk to nonsmoking users., (©2019 American Association for Cancer Research.)

Background: Concomitant use of cannabis and other psychoactive substances is common and it is often difficult to differentiate its acute effects from those of other substances. This study aimed to characterize the acute toxicity of cannabis with and without co-use of other substances., Methods: Retrospective analysis of cases presenting at the emergency departments of three large hospitals in Switzerland due to acute toxicity related to cannabis recreational use., Results: Among 717 attendances related to acute cannabis toxicity, 186 (26 %) were due to use of cannabis alone. The median patient age was 26 years (range 14-68), and 73 % were male. Commonly reported symptoms/signs in lone-cannabis cases included nausea/vomiting (26 %), palpitations (25 %), anxiety (23 %), and chest pain (15 %); there were no fatalities and most intoxications were of minor severity (61 %). Most patients (83 %) using cannabis alone were discharged from the emergency department, 8 % were referred to psychiatric, and two (1 %) to the intensive care; severe complications included psychosis (7 %), coma (6 %), and seizures (5 %) and one patient (<1 %) required intubation. Lone-cannabis patients presented more often with palpitations, anxiety, panic attacks, and chest pain than patients in the co-use group, whereas the latter presented more often with impaired consciousness, agitation, respiratory depression and hallucinations, and were more often admitted to psychiatric or intensive care., Conclusion: Intoxication with cannabis alone was mostly associated with minor toxicity. Nevertheless, severe complications and cases requiring admission to intensive or psychiatric care were also reported, which indicates that intoxication with cannabis alone does not exclude considerable health risks., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims of the Study: To describe the characteristics of cases presenting at the emergency department due to (suspected) poisoning for which consultation on patient management with the national Poisons Information Centre was required., Methods: Retrospective study at the emergency department of Bern University Hospital, Switzerland, from May 2012 to December 2017. Cases were identified in the electronic patient database using appropriate full-text search terms. Cases were excluded if the contact with the National Poisons Information Centre was through an external hospital or directly by the patient. Cases in which the poison centre was not contacted and cases without the patient&rsquo;s general consent to use their medical data for research purposes were also excluded., Results: Overall, 667 cases from the study period were included. The median age was 32 years (range 16&ndash;94); 405 patients (61%) were female and 262 (39%) male. In most cases, the poisoning was acute (n = 631, 95%) and intentional (n = 505, 76%). The most common route of exposure was ingestion (n = 587, 88%) and the most commonly involved substances were sedatives (n = 185, 28%), antidepressants (n = 162, 24%) and non-opioid analgesics (n = 161, 24%). Impaired consciousness was documented in 299 cases (45%). Approximately half of the cases (n = 359, 54%) were of minor severity as assessed using the Poisoning Severity Score, 142 (21%) were of moderate severity, 110 (16%) were asymptomatic and 56 (8%) were severe. There were no fatalities. In most cases (n = 599, 90%), immediate therapeutic or diagnostic measures were undertaken prior to contact with the poison centre. Decontamination measures and specific antidotes undertaken or administered only after contacting the poison centre included whole bowel irrigation, haemodialysis, fomepizole, biperiden, silibinin, deferoxamine, leucovorin, dimercaptopropanesulfonic acid and hydroxocobalamin. Administration of a specific antidote/therapeutic agent was recommended in 87 cases (13%). In 70 of these 87 cases (80%), the specific agents were administered as recommended by the poison centre. In 17 cases (20%), the specific antidotes were not administered as recommended because of either clinical improvement (n = 11), termination of therapy based on laboratory results (n = 3), therapy refused by the patient (n = 2), or identification of a mushroom as non-poisonous (n = 1). In 109 cases (16%), there was no change in patient management after contacting the poison centre., Conclusions: For patients presenting at the emergency department with severe poisoning, contact with the poison information centre can help to implement specific treatment and avoid fatalities. In less severe cases involving more common agents (e.g. paracetamol, benzodiazepines), contact can help to avoid unnecessary treatment and serve as a source of information and/or confirmation.

Aim: To investigate the characteristics of Emergency Department (ED) presentations due to acute paracetamol intoxication., Methods: Retrospective observational study of patients presenting to the ED of Bern University Hospital between May 1, 2012, and October 31, 2018, due to a paracetamol overdose (defined as intake of >4 g/24 h). Cases were identified using the full-text search of the electronic patient database and were grouped into intentional (suicidal/parasuicidal) and unintentional intoxications (e.g., patient unaware of maximal daily dose)., Results: During the study period, 181 cases were included and 143 (79%) of those were intentional. Compared to the patients in the unintentional group, patients in the intentional group were more often female (85% vs 45%, p < 0.001) and younger (median age 23.0 vs 43.5 years, p < 0.001), more frequently suffered from psychiatric comorbidities (93%, (including 49% with borderline personality disorder) vs 24%, p < 0.001), and paracetamol was more often taken as a single dose (80% vs 13%, p < 0.001). Although the median daily ingested dose was lower in the unintentional than in the intentional group (8.2 g vs 12.9 g, p < 0.001), patients in the unintentional group presented later (29% vs 84% within 24 h of ingestion, p < 0.001), included more cases of acute liver failure (nine (24%) vs six (4%), p < 0.001), and were more often hospitalised (24% vs 52% treated as outpatients, p =0.002). There were no significant differences between the groups regarding drug-induced liver injury (seven cases (5%) in the intentional and one (3%) in the unintentional group) or fatalities (one in each group)., Conclusions: The majority of presentations due to paracetamol poisoning were intentional, most commonly in female patients with borderline personality disorder. Patients with unintentional paracetamol intoxication had worse outcomes with respect to acute liver failure and hospitalisation. Future preventive measures should raise awareness of paracetamol toxicity in the general population and encourage particular attention and frequent follow-ups when prescribing paracetamol for vulnerable groups., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2019 Natalia Piotrowska et al.)

Background: Assessing the prevalence and level of exposure (dose) of tobacco and marijuana use is important in studies of harm from use of these substances. We used biochemical analysis of urine to quantitatively assess exposure to nicotine and delta 9-tetrahydrocannabinol (THC) in adolescents receiving medical care in a public hospital METHODS: Participants were 686 adolescents between 12 and 21 years old seen at Zuckerberg San Francisco General Hospital between 2012 and 2014. Urine samples were assayed using high sensitivity liquid chromatographic assays for cotinine, a major metabolite of nicotine, and 11-nor-9-carboxy-delta 9-THC (THC-COOH), a major metabolite of THC. A commonly used immunoassay screen for THC-COOH was also performed., Results: The THC-COOH immunoassay substantially underestimated THC exposure, as measured with the high sensitivity assay. THC use was detected in 25% of participants, with higher prevalence with increasing age and in non-Hispanic blacks. Active tobacco smokers had an 80% prevalence of THC use (odds ratio for cigarette smoking predicting THC use 13.2). Urine cotinine and THC-COOH were significantly correlated (r = 0.60)., Conclusions: The use of a high sensitivity chromatographic urine assay provides a much more complete picture of adolescent tobacco use compared to a commonly used immunoassay. The immunoassay provides high specificity but moderate sensitivity. We confirm high concordance of tobacco and marijuana use and the high predictive value of cigarette smoking in predicting marijuana use, and provide novel data on the quantitative correlation between level of exposure to nicotine and THC. Quantitative screening of nicotine and THC exposure may enhance our understanding of addiction and harm from single and dual product use., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Blacks bear a disproportionate burden of smoking-related diseases and experience greater difficulty quitting smoking than Whites. Nicotine has a high affinity for melanin, and it has been hypothesized that melanin levels might influence nicotine pharmacokinetics and enhance dependence. The aim of this study was to evaluate the hypothesis that melanin affects nicotine disposition kinetics in humans., Methods: Forty-four Black participants were administered intravenous infusions of deuterium-labeled nicotine and cotinine. Plasma concentrations of nicotine and cotinine were measured, and pharmacokinetic parameters were estimated. The constitutive and facultative melanin indexes were measured using a dermaspectrophotometer., Results: The median constitutive melanin index was 60.7 (32.8-134.7) and the median facultative melanin index 68.1 (38.6-127.1). The mean (±SD) nicotine elimination half-life was 136 min (±33.5), clearance was 1237 mL/min (±331), and V ss was 204 L (±66), or 2.6 L/kg (±0.7). No evidence of significant differences was found in nicotine pharmacokinetic parameters by comparing participants in different melanin index quartiles (outliers with very high melanin index had similar pharmacokinetic values to others). Differences were not statistically significant when adjusted for age, BMI, sex and CYP2A6 genotype or the nicotine metabolite ratio (NMR), and no evidence of significant correlations were found between melanin (facultative or constitutive) and the pharmacokinetic parameters of nicotine or cotinine or tobacco dependence measures., Conclusions: Based on our finding in this group of Black smokers, we could not confirm the hypothesis that melanin significantly affects nicotine disposition kinetics or measures of tobacco dependence., (Copyright © 2019. Published by Elsevier B.V.)

Reports of metamizole-induced neutropenia have increased in Switzerland and Germany over the last decades, most likely reflecting increased use of metamizole. To date, there are no effective strategies to identify patients at increased risk of metamizole-induced neutropenia. In this observational, multi-center comparative study, characteristics of patients with metamizole-associated neutropenia were compared with patients treated with metamizole without developing adverse hematological reactions. Patients with metamizole-induced neutropenia treated at the University Hospitals Basel and Bern between 2005 and 2017 were included. Tolerant comparison patients with continuous metamizole treatment (≥500 mg/day for at least 28 days) were recruited from GP offices and community pharmacies. Forty-eight patients with metamizole-induced neutropenia, consisting of 23 and 25 cases with inpatient-acquired and outpatient-acquired neutropenia, respectively, were compared to 39 metamizole tolerant comparison patients. Median latency until first diagnosis of neutropenia was 6 days (1-61 days) in inpatient cases and 19 days (2-204 days) in outpatient cases. There was no association between non-myelotoxic and non-immunosuppressive co-medication (p = .6627), history of drug allergy (p = .1304), and preexisting auto-immune diseases (p = .2313) and the development of metamizole-induced neutropenia. Our results suggest that autoimmune diseases, history of drug allergy, and concomitant treatment with non-myelotoxic and non-immunosuppressive drugs are likely not individual risk factors for metamizole-associated neutropenia., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Aims of the Study: To analyse emergency department (ED) presentations related to acute medical problems after recreational use of prescription/over-the-counter (OTC) drugs in two major Swiss hospitals in order to identify the prevalence of specific drugs, vulnerable groups, time trends and local differences which could have major public health implications., Methods: Retrospective analysis of cases presenting with signs/symptoms consistent with acute toxicity due to recreational use of prescription/OTC drugs from May 2012 to August 2017 at the ED of the University Hospital of Bern and from October 2013 to July 2017 at the ED of the University Hospital Basel. We investigated time trends, sex differences, patient characteristics and consumption patterns within three age groups (&ge;16 to &lt;36 years; &ge;36 to &lt;56 years; &ge;56 years)., Results: During the study period, 344 cases were included out of 1715 ED attendances due to acute drug toxicity and a total of 412,557 ED presentations. The use of prescription drugs in conjunction with illegal drugs was reported in nearly half the cases. The most frequently reported prescription drugs were benzodiazepines (64%, n = 220) and methadone (13%, n = 45). Forty-eight percent (n = 166) of all presentations occurred within the youngest age group. The analysis of time trends showed a significant increase in presentations in the youngest and the oldest groups in Basel (both p &lt;0.05), while the trend remained stable over time in Bern for all age groups. While the number of presentations remained constant over time for men and women in Bern, a significant increase was found for the female cohort in Basel (p &lt;0.05). Patients in all age groups presented with toxicities of predominantly minor severity., Conclusion: The prescription/OTC drugs most frequently leading to ED presentations after recreational use were sedative substances. A large proportion of the patients belonged to the youngest age group. A significant increase in presentations was seen in the youngest and oldest age groups and within women in Basel. This information can be used to inform health care providers so that they can adapt their prevention and treatment strategies in their communities.

1,4-Butanediol (BDO)-used as solvent and abused for its euphoric effects-is converted to gamma-hydroxybutyrate (GHB) by the enzyme alcohol dehydrogenase. This double-blind, placebo-controlled crossover study with six healthy volunteers is the first to date investigating the role of the ADH inhibitor fomepizole (4-methylpyrazole (4MP)) in moderating this conversion in humans. Participants received on two different days either intravenous placebo or 15 mg/kg 4MP followed by oral administration of 25 mg/kg BDO. Pretreatment with 4MP resulted in significantly higher BDO maximal plasma concentration (P = 0.001) and area under the concentration-time curve (AUC; P = 0.028), confirming that ADH is the primary pathway for the conversion of BDO to GHB in humans. With 4MP, the mean arterial pressure was significantly lower at 105 minutes compared to baseline (P = 0.003), indicating that blood pressure lowering, observed not with a temporal relationship to 4MP administration but after the maximum BDO concentration was reached, may be an intrinsic effect of BDO., (© 2018 The Authors Clinical Pharmacology & Therapeutics © 2018 American Society for Clinical Pharmacology and Therapeutics.)

Background: Understanding emergency department and healthcare utilisation related to acute recreational drug toxicity (ARDT) generally relies on nationally collated data based on ICD-10 coding. Previous UK studies have shown this poorly captures the true ARDT burden. The aim of this study was to investigate whether this is also the case elsewhere in Europe., Methods: The Euro-DEN Plus database was interrogated for all presentations 1st July to 31st December 2015 to the EDs in (i) St Thomas' Hospital, London, UK; (ii) Universitätsspital Basel, Basel, Switzerland; and (iii) Zealand University Hospital, Roskilde, Denmark. Comparison of the drug(s) involved in the presentation with the ICD-10 codes applied to those presentations was undertaken to determine the proportion of cases where the primary/subsequent ICD-10 code(s) were ARDT related., Results: There were 619 presentations over the 6-month period. Two hundred thirteen (34.4%) of those presentations were coded; 89.7% had a primary/subsequent ARDT-related ICD-10 code. One hundred percent of presentations to Roskilde had a primary ARDT ICD-10 code compared to 9.6% and 18.9% in Basel and London respectively. Overall, only 8.5% of the coded presentations had codes that captured all of the drugs that were involved in that presentation., Conclusions: While the majority of primary and secondary codes applied related to ARDT, often they did not identify the actual drug(s) involved. This was due to both inconsistencies in the ICD-10 codes applied and lack of ICD-10 codes for the drugs/NPS. Further work and education is needed to improve consistency of use of current ICD-10 and future potential ICD-11 coding systems.

This study investigated the influence of the rate of nicotine metabolism, as indicated by the nicotine metabolite ratio (NMR), on tobacco dependence. We stratified 136 smokers on the basis of saliva NMR as fast (n = 65) and slow (n = 71) metabolizers. Two "loading cigarettes" were smoked after overnight, and a "reward cigarette" was smoked after 6 hours of daytime, abstinence. Blood nicotine concentrations, expired carbon monoxide, withdrawal/craving, and reward questionnaires were collected before/after smoking and during daytime abstinence. Compared with slow metabolizers, fast metabolizers had a shorter nicotine elimination half-life (P < 0.001), lower plasma nicotine concentrations (P < 0.001), and higher withdrawal/craving scores (P < 0.05) for most times during daytime abstinence, indicating that fast metabolizers are likely smoking more to relieve withdrawal symptoms (negative reinforcement). Reward/satisfaction scores were similar in fast and slow metabolizers, suggesting that faster nicotine metabolism, assessed by NMR, is not associated with greater positive reinforcement. CYP2A6 normal (n = 82) and reduced (n = 42) genotype predicted plasma nicotine concentrations but not withdrawal symptoms., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

The consequences of mushroom poisoning range from mild, mostly gastrointestinal, disturbances to organ failure or even death. This retrospective study describes presentations related to mushroom poisoning at an emergency department in Bern (Switzerland) from January 2001 to October 2017. Gastrointestinal disturbances were reported in 86% of the 51 cases. The National Poisons Information Centre and mycologists were involved in 69% and 61% of the cases, respectively. Identification of the mushroom type/family was possible in 43% of the cases. The most common mushroom family was Boletaceae (n = 21) and the most common mushrooms Xerocomus chrysenteron (n = 7; four being part of a cluster), Clitocybe nebularis , Lepista nuda and Lactarius semisanguifluus (n = 5 each, four being part of a cluster). Poisonous mushrooms included Amanita phalloides (n = 3, all analytically confirmed), Boletus satanas (n = 3), Amanita muscaria (n = 2) and Amanita pantherina (n = 2). There were no fatalities and 80% of the patients were discharged within 24 h. Mushroom poisoning does not appear to be a common reason for emergency consultation and most presentations were of minor severity and related to edible species (e.g., due to incorrect processing). Nevertheless, poisonous mushrooms and severe complications were also recorded. Collaboration with a poison centre and/or mycologists is of great importance, especially in high risk cases.

Rationale: Gamma-hydroxybutyrate acid (GHB), a GABA B receptor agonist approved for treatment of narcolepsy, impairs driving ability, but little is known about doses and plasma concentrations associated with impairment and time course of recovery., Objective: To assess effects of oral GHB (Xyrem®) upon driving as measured by a driving simulator, and to determine plasma concentrations associated with impairment and the time course of recovery., Methods: Randomized, double-blind, two-arm crossover study, during which 16 participants received GHB 50 mg/kg orally or placebo. GHB blood samples were collected prior to and at 1, 3, and 6 h post dosing. Driving simulator sessions occurred immediately after blood sampling., Results: Plasma GHB was not detectable at baseline or 6 h post dosing. Median GHB concentrations at 1 and 3 h were 83.1 mg/L (range 54-110) and 24.4 mg/L (range 7.2-49.7), respectively. Compared to placebo, at 1 h post GHB dosing, significant differences were seen for the life-threatening outcome collisions (p < 0.001) and off-road accidents (p = 0.018). Although driving was not faster, there was significantly more weaving and erratic driving with GHB as measured by speed deviation (p = 0.002) and lane position deviation (p = 0.004). No significant impairment regarding driving outcomes was found in the GHB group at 3 and 6 h post dose., Conclusion: GHB in doses used to treat narcolepsy resulted in severe driving impairment at 1 h post dosing. After 3 to 6 h, there was full recovery indicating that safe driving is expected the next morning after bedtime therapeutic GHB use in the absence of other substances.

Background: Psychoactive substances are often regarded as causal factors contributing to violent injuries, sexual abuse and homicides. While these effects have been demonstrated for some substances (e.g. cocaine), current available data for others are more controversial (e.g. cannabis) or very limited (e.g. ecstasy)., Aims of the Study: To collect data on the type and frequency of psychoactive substance use in cases of emergency department (ED) presentations related to interpersonal violence., Methods: Retrospective study at the University Hospital of Bern, Switzerland, between May 2012 and June 2016. The study covered cases of violent crime associated with psychoactive substances. Cases of isolated ethanol intoxication, suicide attempts, and substance use for medical purposes were excluded., Results: The study included 103 cases among the 164,846 ED attendances. In the majority of the cases, the type of violence was bodily force (52%) related to urban violence (83%). The mean patient age was 29 years and 79% were male. 63% of the patients reported use of more than one drug; alcohol co-use was reported in 60% of the cases. Besides alcohol, the substances most often reported were cannabis (50%) and cocaine (21%). Alcohol and cannabis was also the most commonly reported substance combination (36% of the total cases). Urine drug screening was performed in 34% of the cases and cannabis and cocaine were the most commonly detected substances (46% and 19%, respectively). There were no cases of novel substances. 23% of the patients were admitted to a hospital ward, 10% to a psychiatric clinic., Conclusion: Cannabis and cocaine were, besides alcohol, the substances most often reported in ED presentations related to offences of violence. Because of the high prevalence of alcohol co-use, no final conclusions can be drawn on the contribution of single substances.

The aim of the study was to compare self-reported and analytically confirmed substance use in cases of acute recreational drug toxicity.We performed a retrospective analysis of emergency department presentations of acute recreational drug toxicity over 2 years (October 2013 to September 2015) within the European Drug Emergencies Network Plus project.Among the 10,956 cases of acute recreational drug toxicity during the study period, 831 could be included. Between the self-reported substance use and the toxicological results, the highest agreement was found for heroin (86.1%) and cocaine (74.1%), whereas inhalants, poppers, and magic mushrooms were self-reported but not analytically detected. Cathinones and other new psychoactive substances (NPS) could be detected using additional analytical methods. Among cases with both immunoassay (IA) and confirmation with mass spectrometry (MS), the results were consistent for methadone (100%) and cocaine (95.5%) and less consistent for amphetamines (81.8%). In cases with a positive IA for amphetamines (n = 54), MS confirmed the presence of 3,4-methylenedioxymethamphetamine (MDMA), amphetamine, methamphetamine, and NPS in 37, 20, 10, and 6 cases, respectively, also revealing use of more than 1 substance in some cases. MS yielded positive results in 21 cases with a negative IA for amphetamines, including amphetamine, MDMA, methamphetamine, and NPS, in 14, 7, 2, and 2 cases, respectively.In conclusion, the highest agreement was found between self-reports and analytical findings for heroin and cocaine. The diagnosis of NPS use was mainly based on self-report. The IAs accurately identified methadone and cocaine, and MS had advantages for the detection of NPS and amphetamine derivatives.

Background and Purpose: Opioids may inhibit the 5-HT transporter (SERT) and the noradrenaline transporter (NET). NET inhibition may contribute to analgesia, and SERT inhibition or interactions with 5-HT receptors may cause serotonergic toxicity. However, the effects of different opioids on the human SERT, NET and 5-HT receptors have not been sufficiently studied., Experimental Approach: We determined the potencies of different opioids to inhibit the SERT and NET in vitro using human transporter-transfected HEK293 cells. We also tested binding affinities at 5-HT 1A , 5-HT 2A and 5-HT 2C receptors. Additionally, we assessed clinical cases of the serotonin syndrome associated with each opioid reported by PubMed and a World Health Organization database., Key Results: Dextromethorphan, l(R)-methadone, racemic methadone, pethidine, tramadol and tapentadol inhibited the SERT at or close to observed drug plasma or estimated brain concentrations in patients. Tapentadol was the most potent NET inhibitor. Pethidine, tramadol, l(R)-methadone, racemic methadone, dextromethorphan and O-desmethyltramadol also inhibited the NET. 6-Monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, heroin, hydrocodone, hydromorphone, morphine, oxycodone and oxymorphone did not inhibit the SERT or NET. Fentanyl interacted with 5-HT 1A receptors and methadone, pethidine and fentanyl with 5-HT 2A receptors, in the low micromolar range. Opioids most frequently associated with the serotonin syndrome are tramadol, fentanyl, tapentadol, oxycodone, methadone and dextromethorphan., Conclusions and Implications: Some synthetic opioids interact with the SERT and NET at potentially clinically relevant concentrations. SERT inhibition by tramadol, tapentadol, methadone, dextromethorphan and pethidine may contribute to the serotonin syndrome. Direct effects on 5-HT 1A and/or 5-HT 2A receptors could be involved with methadone and pethidine., (© 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Considering the negative effects of stress on health, there is a growing interest in stress-reducing interventions. The present study examines the effects of a fixed combination of valerian, passion flower, lemon balm, and butterbur extracts (Ze 185) on biological and affective responses to a standardized psychosocial stress paradigm., Purpose: The aim of the present study was to investigate the efficacy of Ze 185 on cortisol and anxiety stress responses to acute psychosocial stress in healthy subjects., Study Design: This study was a randomized, placebo-controlled, double blind study with 3 parallel groups., Methods: 72 healthy male participants were randomized to 3 groups (Ze 185, placebo or no treatment) during 4 days prior to a standardized psychosocial stress paradigm. Principle outcomes were salivary cortisol and self-reported anxiety responses to stress assessed at the fourth day., Results: The stress paradigm induced significant and large cortisol and self-reported anxiety responses. Groups did not differ significantly in their salivary cortisol response to stress, but participants in the Ze 185 condition showed significantly attenuated responses in self-reported anxiety in comparison to placebo (F(3, 41) = 3.33, p = 0.03) and no treatment (F(3, 43) = 2.77, p = 0.05)., Conclusion: The results show that Ze 185 significantly attenuated the subjective emotional stress response during an acute stress situation, without affecting biological stress responses. Given that a circumscribed biological stress response is to be considered as an adaptive mechanism, Ze 185 reduces self-reported anxiety response to stress without affecting assumingly adaptive biological stress responses., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

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

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

Background: Although the recreational use of psychoactive substances is common there is only limited systematic collection of data on acute drug toxicity or hospital presentations. Currently, data from Switzerland are only available from the University Hospital of Basel. The present study aimed to describe the presentations due to recreational drug use at an emergency department in Bern, Switzerland during a 4 year period., Methods: Retrospective analysis of cases presenting from May 2012 to April 2016 at the emergency department of the University Hospital of Bern, Switzerland, with symptoms/signs consistent with acute toxicity of recreational drug use. The cases were retrieved using a comprehensive full-text search algorithm of the electronic health records. Isolated ethanol intoxications were excluded., Results: During the study period, 503 of the 157,328 emergency department attendances were directly related to acute toxicity of substances used recreationally. The mean patient age was 33 years (range 16-74), 68% were male. Alcohol co-ingestion was reported in 54% of the cases, and use of more than one recreational drug in 37% of the cases. Most presentations were related to cocaine (29%), cannabis (26%), heroin (20%) and benzodiazepines/sedatives (18%). Urine drug screening immunoassay was available in 277 cases (55%). The most frequently detected substances were cannabis (29%), cocaine (22%), benzodiazepines (21%) and opioids excluding methadone (20%). There were only two intoxications with novel psychoactive substances (NPSs): One with methylone and one with 2,5-dimethoxy-4(n)-propylphenethylamine (2C-P). The majority of patients (58%) displayed impaired consciousness (Glasgow Coma Scale (GCS) <15) upon presentation and/or pre-hospital; 21% were unconscious (GCS <8). Other frequent symptoms were agitation (36%), tachycardia (29%), and anxiety (24%). Severe complications included two fatalities, three acute myocardial infarctions, two intracranial haemorrhages, as well as psychosis and seizures in 71 and 26 cases, respectively., Conclusions: Most medical problems related to recreational drug use were associated with cocaine and cannabis use and were mainly characterised by central nervous system depression, sympathomimetic toxicity and/or psychiatric disorders. Presentations related to acute toxicities of NPSs appear to be uncommon, while prescription drugs were after classical recreational drugs the substances most commonly reported.

2,5-Dimethoxy-4(n)-propylphenethylamine (2C-P) is a synthetic phenethylamine derivative belonging to the large family of the so-called 2C drugs. These compounds can differ significantly in receptor affinity, potency and duration of action, and an important structural difference is the ligand in the 4 position of the phenyl ring, such as propyl in 2C-P or bromine in 2,5-dimethoxy-4-bromophenethylamine (2C-B). The 2C drugs are known for their hallucinogenic properties. We present a case of a 19-year-old male admitted to the emergency department with severe hallucinations, mydriasis, tachycardia, agitation and confusion following the use of a substance sold as 2C-B. By using liquid chromatography-mass spectrometry, the more potent substance 2C-P was detected and quantified. On the basis of two blood sample concentrations, the estimated elimination half-life was 19 h. This case report illustrates and discusses the differences in potency and duration of action of 2C drugs., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)