Previous studies have questioned the integrity of drug promotional material from the pharmaceutical industry to medical professionals. Herein, we present the result of repeated monitoring of adherence to legal requirements regulating marketing mailings from pharmaceutical companies to Norwegian general practitioners over three separate time periods in 2004, 2012 and 2023-24. The claims made in the mailings were compared to the sources cited and evaluated in accordance with the governmental regulations. Pertinent information about conflicts of interest was registered and considered. A considerable decline in the number of mailings acquired over time was noted. The proportion of claims defined as correct and clinically relevant according to the legal definition was 48

Systematic retrospective processing of previously analysed biological samples has been proven to be a valuable tool in the search for new drugs (e.g. new psychoactive substances (NPS)) and for quality assessment in clinical and forensic toxicology. In a previous study, we developed a strategy for retrospective data-analysis using a personalized library of synthetic cannabinoids, designer benzodiazepines and synthetic opioids obtained from the crowdsourced database HighResNPS (https://highresnps.com). In this study, the same strategy was employed for the compounds within the groups of NPS that were not previously included such as synthetic cathinones, phenethylamines, aminoindanes, arylalkylamines, piperazine derivates, piperidines, pyrrolidines, indolalkylamines and arylcyclohexylamines. Synthetic opioids and designer benzodiazepines, which were not part of the previous study, were also included. To enhance the effectiveness of the retrospective analysis, a predicted retention time was included for all entries. Data files from the analysis of 2186 forensic post mortem samples with an Agilent Technologies 6540 ultra-high pressure liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) performed in the laboratory from January 2014 to December 2021 were retrospectively processed with the up-to-date library. Tentative findings were classified in two groups: The findings where MS/MS data was acquired for library match (category 1) and the less certain findings where such data lacked (category 2). Five compounds of category 1 (three synthetic cathinones and two indolalkylamines) were identified in 12 samples. Only one of the findings, 4-MEAPP (4-methyl-α-ethylaminopentiophenone), was deemed plausible after reviewing case information. As many as 501 presumably positive category 2 findings were detected. Using the predicted retention time as an additional criterion the number was significantly reduced but still too high for a manual review. This work has demonstrated that the strategy developed in the previous study can be applied to other NPS groups. However, it is important to note the limitations such a method may have in detecting compounds at very low concentrations.

Rocuronium is a neuromuscular blocking agent mainly used in anesthetic procedures. Two patients who died 53 and 76 days, respectively, after their last rocuronium exposure had low (0.002-0.0 07 mg/L) levels of the drug in femoral blood, urine and vitreous humor samples obtained at autopsy. In neither case, the cause of death was related to the exposure to rocuronium. Here, these two cases are presented and the im-plications of the findings discussed. (c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

BAKGRUNN BAKGRUNN Avvik i bruk og håndtering av legemidler er ikke uvanlig. Det finnes lite oppdatert informasjon om legemiddelavvik i norske sykehus. MATERIALE OG METODE MATERIALE OG METODE Alle uønskede hendelser ved St. Olavs hospital er pålagt intern meldeplikt via et elektronisk skjema. Vi har for treårsperioden 2015–17 systematisert registrerte legemiddelavvik i databasen der rapportene lagres, og sammenlignet med tall fra en tilsvarende studie gjennomført i årene 2002–06. RESULTATER RESULTATER Totalt 1 604 legemiddelavvik ble registrert, fordelt på 1 587 meldinger. Doseringsavvik dominerte (n = 1 070; 67 %), etterfulgt av at det hadde blitt gitt et annet legemiddel enn ordinert (n = 175; 11 %). Majoriteten var av ubetydelig eller lav alvorlighetsgrad. Det var en overhyppighet av rapportering blant de yngste og de eldste pasientene. 79 % av avvikene ble meldt av sykepleiere. Uoppmerksomhet/forglemmelse (15 %), stress/travelhet (12 %), slurvete kurveføring (10 %) og feil/uklar ordinering (10 %) ble oppgitt som de vanligste årsakene. FORTOLKNING FORTOLKNING Antallet meldinger om legemiddelavvik er økende, men det er usikkert hvor store mørketallene er. Avvikstypene og fordelingen mellom dem er den samme som i tidligere studier. De underliggende årsakene er også velkjente. Utfordringen ligger i å hindre at slike forhold oppstår.

BACKGROUND:Errors in the use and administration of medicinal drugs are not uncommon. There is little up-to-date information available on medication errors in Norwegian hospitals. MATERIAL AND METHOD:It is compulsory to report all adverse events internally at St Olav's Hospital via an electronic form. For the three-year period 2015-2017 we have reviewed all medication errors in the database where the reports are stored and compared them with figures from a similar study conducted in the period 2002-2006. RESULTS:Altogether 1604 medication errors were registered, distributed among 1587 reports. Dosing errors were most common (n=1070; 67 %), followed by administration of another drug than prescribed (n=175; 11 %). Most errors were of an insignificant or low degree of severity. There was a preponderance of reporting among the youngest and the oldest patients. 79 % of the errors were reported by nurses. Inattention/forgetfulness (15 %), stress/high workload (12 %), sloppy documentation in drug charts (10 %) and erroneous/unclear prescribing (10 %) were reported as the most frequent causes. INTERPRETATION:The number of reports of medication errors is increasing, but the extent of underreporting is uncertain. The types of errors and their distribution are similar to previous studies. The underlying causes are also well known; the challenge is to prevent these situations from arising.

The introduction of new psychoactive substances (NPS) on the illicit drug market has led to major challenges for the analytical laboratories. Keeping screening methods up to date with all relevant drugs is hard to achieve and the risk of missing important findings in biological samples is a matter of concern. Aiming for an extended retrospective data analysis, diagnostic fragment ions from synthetic cannabinoids (n=251), synthetic opioids (n=88) and designer benzodiazepines (n=26) not included in our original analytical method were obtained from the crowdsourced database HighResNPS.com and converted to a personalized library in a format compatible with the analytical instrumentation. Data files from the analysis of 1314 forensic post mortem samples with an Agilent 6540 ultra high pressure liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) performed in our laboratory from January 2014 to December 2018 were retrieved and retrospectively processed with the new personalized library. Potentially positive findings were grouped in two: The most confident findings contained MS/MS data for library match (category 1) whereas the less confident findings lacked such data (category 2). Five new category 1 findings were identified: Flubromazepam in two data files from 2015 and 2016, respectively, phenibut (4-amino-3-phenylbutyric acid) in one data file from 2015, fluorofentanyl in one data file from 2016 and cyclopropylfentanyl in one data file from 2018. Retention time matches with reference standards further strengthened these findings. A list of 35 presumably positive category 2 findings was generated. Of these, only one finding of phenibut was considered plausible after checking retention times and signal-to-noise ratios. This study shows that new compounds can be detected retrospectively in data files from QTOF-MS using an updated library containing diagnostic fragment ions. Automatic screening procedures can be useful, but a manual re-evaluation of positive findings will always be necessary.

The antipsychotic drug quetiapine is widely used, and increasingly prescribed off-label. Furthermore, quetiapine use has been linked to increased mortality rates, most likely due to a range of cardiovascular and metabolic adverse effects. This makes quetiapine a relevant substance in forensic toxicology casework. Quetiapine is believed to undergo significant post mortem redistribution. Herein, we present tissue distribution and concentration levels of quetiapine in post mortem whole blood, brain tissue, skeletal muscle, and liver tissue in a series of 14 quetiapine-implicated forensic autopsy cases along with the quetiapine concentrations determined in femoral whole blood in conjunction with the autopsies. Quantification was performed using liquid-liquid extraction and a validated UPLC-MSMS method. Six deaths were attributed to intoxication with quetiapine in combination with other substances; there were no quetiapine monointoxications. In eight cases, death was attributed to other causes than drug toxicity. In a majority of the cases, liver tissue contained the highest quetiapine concentrations, while whole blood levels were the lowest. Central (heart) blood concentrations were generally higher than peripheral (femoral) blood levels. Quetiapine concentrations in femoral blood correlated most strongly with concentrations in skeletal muscle. Otherwise, there was no consistent hierarchy of quetiapine tissue concentrations, and the tissue distribution showed no clear relationship with the length of the post mortem interval.

Psychotropic drugs are regularly present in cases of sudden, unexpected death. Such drugs also tend to express significant postmortem redistribution. To facilitate further investigation of this phenomenon, reliable quantitative methods applicable to multiple biological matrices are needed. We present a validated ultra-performance liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of quetiapine, clozapine and mirtazapine in postmortem whole blood, skeletal muscle, brain tissue and liver tissue using high-performance liquid chromatography-tandem mass spectrometry. Sample preparation was performed using liquid-liquid extraction. The validated ranges were 3.8-1534, 16-1960 and 13-1060 μg/L for quetiapine, clozapine and mirtazapine, respectively. Within-run and between-run accuracy (87.4-122%) and precision (CV 1.5-8.9%), matrix effects (95-101%) and recovery (35.7-92%) were validated at two concentration levels; 5.8 and 1227 μg/L for quetiapine, 25 and 1568 μg/L for clozapine and 20 and 849 μg/L for mirtazapine. Stability in a 10°C environment was assessed for treated samples of brain, liver and muscle tissue, showing deviations in analyte concentrations ranging from -8% to 9% after 3 days. The analyte concentrations in treated samples of whole blood stored at 4°C deviated by <5% after 5 days. The method was applied in three forensic autopsy cases implicating quetiapine, clozapine and mirtazapine, respectively, in supratherapeutic concentrations.

Hans Cato ble født på Røros. Han tok sin medisinske grunnutdannelse og ph.d. ved Universitetet i Edinburgh. Etter en periode som dosent ved Universitetet i Bergen ble han tilsatt som den første professoren i farmakologi da medisinutdanningen startet opp i Trondheim i 1975 ved det som den gang het Avdeling for medisin. Han var en av pionerene i denne etableringen og var ikke redd for å ta ansvar. Han ble dermed en nøkkelperson i oppbyggingen av medisinstudiet. I 1984 fikk Avdeling for medisin status som medisinsk fakultet ved Universitetet i Trondheim, noe Hans Cato hadde lagt ned et betydelig arbeid for å få til, ikke minst i perioden som dekan i årene 1981–85.

BACKGROUND Since their introduction more than 50 years ago, use of β-agonists for inhalation has been associated with increased mortality. Since the turn of the century, particular concern has been voiced regarding long-acting β2-selective agonists. Our purpose was to investigate the evidence from recently published randomised trials of possible increased risks of death and serious adverse events related to exposure to these drugs. MATERIAL AND METHOD A PubMed search identified ten clinical trials which fulfilled predefined inclusion criteria. RESULTS The ten trials encompassed 66 664 patients. A total of 16 asthma-related deaths after exposure to long-acting β2-selective agonists were recorded among 33 043 actively treated patients, whereas four such deaths were recorded among the 33 621 patients in the control groups. A single, large, pragmatic trial accounts for a majority of these fatalities. INTERPRETATION Exposure to long-acting β2-selective agonists is associated with a small increase in mortality. Whether concomitant use of inhalation steroids fully reverses this effect is not clear.