Publications by authors named "Evangelia Liakoni"

44 Publications

The Risk of Muscular Events Among New Users of Hydrophilic and Lipophilic Statins: an Observational Cohort Study.

J Gen Intern Med 2021 Mar 9. Epub 2021 Mar 9.

Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.

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.
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http://dx.doi.org/10.1007/s11606-021-06651-6DOI Listing
March 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

Effect of race and glucuronidation rates on the relationship between nicotine metabolite ratio and nicotine clearance.

Pharmacogenet Genomics 2021 07;31(5):97-107

Department of Medicine, Program in Clinical Pharmacology, Division of Cardiology, University of California, San Francisco, California, USA.

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.
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http://dx.doi.org/10.1097/FPC.0000000000000427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184575PMC
July 2021

Development and validation of a prognostic COVID-19 severity assessment (COSA) score and machine learning models for patient triage at a tertiary hospital.

J Transl Med 2021 02 5;19(1):56. Epub 2021 Feb 5.

Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

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.
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http://dx.doi.org/10.1186/s12967-021-02720-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862984PMC
February 2021

Retrospective analysis of adverse drug reactions leading to short-term emergency hospital readmission.

Swiss Med Wkly 2021 Jan 20;151:w20400. Epub 2021 Jan 20.

Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland / Institute of Pharmacology, University of Bern, Switzerland.

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.
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http://dx.doi.org/10.4414/smw.2021.20400DOI Listing
January 2021

Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations.

Genes (Basel) 2020 10 29;11(11). Epub 2020 Oct 29.

Department of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland.

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 ( < 1 × 10) 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, = 1.01 × 10) and rs4427239 (OR = 5.47, 95%CI: 2.81-10.65, = 5.75 × 10), of which the latter is located in the 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.
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http://dx.doi.org/10.3390/genes11111275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716224PMC
October 2020

High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis.

Front Genet 2020 21;11:951. Epub 2020 Aug 21.

Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

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. A case-control cohort of Swiss patients with a history of neutropenia or agranulocytosis associated with metamizole exposure ( = 53), metamizole-tolerant ( = 39) and unexposed controls ( = 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 ( = 31 cases, = 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 , -, and - using the HLA-specific mapper . Eight candidate alleles ( < 0.05) were identified in the discovery subset, of which - was associated with MIA in the full Swiss cohort ( < 0.01) restricted to agranulocytosis (ANC < 0.5 × 10/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. 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.
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http://dx.doi.org/10.3389/fgene.2020.00951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473498PMC
August 2020

Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans.

Br J Clin Pharmacol 2021 03 25;87(3):1466-1474. Epub 2020 Oct 25.

Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.

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 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 (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.
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http://dx.doi.org/10.1111/bcp.14553DOI Listing
March 2021

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

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

Characteristics of emergency department presentations requiring consultation of the national Poisons Information Centre.

Swiss Med Wkly 2019 Dec 17;149:w20164. Epub 2019 Dec 17.

Department of Emergency Medicine, Inselspital, University Hospital Bern, University of Bern, Switzerland.

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’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 16–94); 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.
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http://dx.doi.org/10.4414/smw.2019.20164DOI Listing
December 2019

Emergency department presentations related to acute toxicity following recreational use of cannabis products in Switzerland.

Drug Alcohol Depend 2020 01 7;206:107726. Epub 2019 Nov 7.

Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse 15, 3010 Bern, Switzerland; Institute of Pharmacology, University of Bern, Freiburgstrasse 15, 3010, Bern, Switzerland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.drugalcdep.2019.107726DOI Listing
January 2020

Effects of Nicotine Metabolic Rate on Cigarette Reinforcement.

Nicotine Tob Res 2020 07;22(8):1419-1423

Program in Clinical Pharmacology, Division of Cardiology, Department of Medicine, University of California San Fransisco, San Francisco, CA.

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.
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http://dx.doi.org/10.1093/ntr/ntz210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364822PMC
July 2020

Quantitative biochemical screening for marijuana use and concordance with tobacco use in urban adolescents.

Drug Alcohol Depend 2019 12 25;205:107583. Epub 2019 Sep 25.

Department of Laboratory Medicine, University of California, San Francisco, CA United States.

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.
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http://dx.doi.org/10.1016/j.drugalcdep.2019.107583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893148PMC
December 2019

Comparison of Systemic Exposure to Toxic and/or Carcinogenic Volatile Organic Compounds (VOC) during Vaping, Smoking, and Abstention.

Cancer Prev Res (Phila) 2020 02 25;13(2):153-162. Epub 2019 Sep 25.

Clinical Pharmacology Research Program, Division of Cardiology, Zuckerberg San Francisco General Hospital, Department of Medicine, University of California, San Francisco, California.

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 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.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007368PMC
February 2020

Relationship between skin melanin index and nicotine pharmacokinetics in African American smokers.

Drug Alcohol Depend 2019 11 30;204:107474. Epub 2019 Aug 30.

Clinical Pharmacology Research Program, Division of Cardiology, Zuckerberg San Francisco General, Department of Medicine, University of California, San Francisco, CA 94143-1220, USA; Center for Tobacco Control Research and Education, University of California, San Francisco, CA 94143-1390, USA.

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 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.
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http://dx.doi.org/10.1016/j.drugalcdep.2019.04.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272190PMC
November 2019

Clinical value of analytical testing in patients presenting with new psychoactive substances intoxication.

Br J Clin Pharmacol 2020 03 17;86(3):429-436. Epub 2019 Dec 17.

Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

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.
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http://dx.doi.org/10.1111/bcp.14115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080633PMC
March 2020

Metamizole-associated neutropenia: Comparison of patients with neutropenia and metamizole-tolerant patients.

Eur J Intern Med 2019 Oct 3;68:36-43. Epub 2019 Aug 3.

Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital Bern University Hospital, University of Bern, Freiburgstrasse 18, 3010 Bern, Switzerland; Institute of Pharmacology, University of Bern, Freiburgstrasse 18, 3010 Bern, Switzerland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejim.2019.07.029DOI Listing
October 2019

Emergency department presentations related to abuse of prescription and over-the-counter drugs in Switzerland: time trends, sex and age distribution.

Swiss Med Wkly 2019 Jul 24;149:w20056. Epub 2019 Jul 24.

Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland / Institute of Pharmacology, University of Bern, Switzerland.

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 (≥16 to <36 years; ≥36 to <56 years; ≥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 <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 <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.
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http://dx.doi.org/10.4414/smw.2019.20056DOI Listing
July 2019

Emergencies related to recreational drug abuse in Spain compared to emergencies attended in 3 European areas.

Emergencias 2018 Dic;30(6):385-394

Área de Urgencias, Hospital Clínic, Barcelona; Grupo de Investigación "Urgencias: Procesos y Patologías", IDIBAPS, Barcelona, España.

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.
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July 2019

Poor Identification of Emergency Department Acute Recreational Drug Toxicity Presentations Using Routine Hospital Coding Systems: the Experience in Denmark, Switzerland and the UK.

J Med Toxicol 2019 04 2;15(2):112-120. Epub 2019 Jan 2.

Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, St Thomas' Hospital, 3rd Floor, Block C, South Wing, Westminster Bridge Road, London, SE1 7EH, UK.

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.
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http://dx.doi.org/10.1007/s13181-018-0687-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440929PMC
April 2019

Mushroom Poisoning-A 17 Year Retrospective Study at a Level I University Emergency Department in Switzerland.

Int J Environ Res Public Health 2018 12 14;15(12). Epub 2018 Dec 14.

Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland.

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 (n = 7; four being part of a cluster), , and (n = 5 each, four being part of a cluster). Poisonous mushrooms included (n = 3, all analytically confirmed), (n = 3), (n = 2) and (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.
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http://dx.doi.org/10.3390/ijerph15122855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313731PMC
December 2018

Butanediol Conversion to Gamma-Hydroxybutyrate Markedly Reduced by the Alcohol Dehydrogenase Blocker Fomepizole.

Clin Pharmacol Ther 2019 05 8;105(5):1196-1203. Epub 2019 Jan 8.

Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, University of California, San Francisco, California, USA.

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.
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http://dx.doi.org/10.1002/cpt.1306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465153PMC
May 2019

Effects of Nicotine Metabolic Rate on Withdrawal Symptoms and Response to Cigarette Smoking After Abstinence.

Clin Pharmacol Ther 2019 03 25;105(3):641-651. Epub 2018 Oct 25.

Division of Clinical Pharmacology and Experimental Therapeutics, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

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.
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http://dx.doi.org/10.1002/cpt.1238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967935PMC
March 2019

Effect of γ-hydroxybutyrate (GHB) on driving as measured by a driving simulator.

Psychopharmacology (Berl) 2018 Nov 19;235(11):3223-3232. Epub 2018 Sep 19.

Departments of Medicine and Bioengineering & Therapeutic Sciences, The University of California San Francisco, San Francisco, CA, USA.

Rationale: Gamma-hydroxybutyrate acid (GHB), a GABA 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.
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http://dx.doi.org/10.1007/s00213-018-5025-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457903PMC
November 2018

Psychoactive substances and violent offences: A retrospective analysis of presentations to an urban emergency department in Switzerland.

PLoS One 2018 29;13(3):e0195234. Epub 2018 Mar 29.

Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195234PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875877PMC
July 2018

Effects of a fixed herbal drug combination (Ze 185) to an experimental acute stress setting in healthy men - An explorative randomized placebo-controlled double-blind study.

Phytomedicine 2018 Jan 12;39:85-92. Epub 2017 Dec 12.

Division of Clinical Psychology and Psychotherapy, Faculty of Psychology, University of Basel, Missionsstrasse 62, 4055 Basel, Switzerland.

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.
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http://dx.doi.org/10.1016/j.phymed.2017.12.005DOI Listing
January 2018

Acute recreational drug toxicity: Comparison of self-reports and results of immunoassay and additional analytical methods in a multicenter European case series.

Medicine (Baltimore) 2018 02;97(5):e9784

Division of Clinical Pharmacology and Toxicology, Basel University Hospital and University of Basel, Basel, Switzerland Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern Clinical Toxicology Unit, Emergency Department, Hospital Universitari Son Espases, Research Institute of Health Sciences (IdISBa), Palma de Mallorca, Spain Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners Clinical Toxicology, Faculty of Life Sciences and Medicine, King's College London, London, UK The Norwegian CBRNe Centre of Medicine, Department of Acute Medicine, Oslo University Hospital, Oslo, Norway Department of Clinical Toxicology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

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.
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http://dx.doi.org/10.1097/MD.0000000000009784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805445PMC
February 2018

Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome.

Br J Pharmacol 2018 02 6;175(3):532-543. Epub 2018 Jan 6.

Clinical Pharmacology and Toxicology, Department of Biomedicine, Department of Internal Medicine, University Hospital Basel, University of Basel, Basel, Switzerland.

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 , 5-HT and 5-HT 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 receptors and methadone, pethidine and fentanyl with 5-HT 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 and/or 5-HT receptors could be involved with methadone and pethidine.
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http://dx.doi.org/10.1111/bph.14105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773950PMC
February 2018

Recreational use of carfentanil - a case report with laboratory confirmation.

Clin Toxicol (Phila) 2018 02 31;56(2):151-152. Epub 2017 Jul 31.

a Department of Nephrology, Hypertension and Clinical Pharmacology , Inselspital, Bern University Hospital, University of Bern , Bern , Switzerland.

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http://dx.doi.org/10.1080/15563650.2017.1355464DOI Listing
February 2018
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