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Two challenges in detecting γ-hydroxybutyric acid (GHB) intake are its endogenous presence and in vitro production after sampling. This study developed an LC-MS/MS method for selective GHB determination in human antemortem blood, urine, and oral fluid at endogenous concentrations. Furthermore, the stability of GHB in blood samples and its endogenous concentrations in samples taken under controlled circumstances were investigated. Samples were extracted in methanol/acetonitrile and processed by anion exchange solid-phase extraction. GHB was separated from structural isomers using a reversed-phase LC column with anion properties. The validated limit of quantification was 0.005 µg/mL in blood and 0.010 µg/mL in urine and oral fluid, at which the relative reproducibility standard deviation and bias were <15 %. The mean extraction recovery was ≥90 %. The average GHB concentration increased by 1.2 µg/mL in fluoride/citrate- preserved blood after 28 days of storage at 4°C; however, in fluoride/oxalate (FX)-preserved blood, the mean concentration increased by only 0.055 µg/mL. No change was observed at -20°C. In 105 randomly selected samples of FX-preserved blood collected for forensic antemortem toxicological analysis, all concentrations were <0.066 µg/mL, even after long-term storage at -20°C. In blood, urine, and oral fluid samples from a clinical study of GHB intake, endogenous baseline levels from 30 participants ranged from 0.0069-0.050, 0.024-0.38, and 0.034-0.93 µg/mL, respectively. These results demonstrate that the current cut-off level of 5 µg/mL for discriminating between endogenous and exogenous GHB in antemortem blood could be considerably lower for FX-preserved blood stored at -20°C., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Knowledge of opioid tolerance in a deceased person is important for distinguishing between therapeutic and toxic opioid concentrations for that particular individual when interpreting postmortem toxicological results. However, no biomarkers for opioid tolerance are currently available. This review aimed to study the existing literature on mechanisms or changes in signaling pathways related to chronic opioid use, which could be relevant for further studies to identify biomarkers for opioid tolerance. We performed a systematic literature search using the PRISMA 2020 guidelines using the MeSH terms "opioid tolerance AND biomarkers" in PubMed, Embase, WebofScience, and the Cochrane library. A review of the search results yielded seven studies on animal models or humans, identifying and evaluating thirteen possible biomarkers in terms of specificity for changes induced by opioids and other aspects to be considered as potential biomarkers. We evaluated nine potential biomarkers as unlikely to be specific for opioid tolerance, and one had contradictory results in terms of upregulation or downregulation. However, methylation of the promoter region of the μ-opioid receptor gene, increased activity of soluble puromycin-sensitive aminopeptidase, altered miRNA profile, or other multiple component profiling may be interesting to study further as biomarkers for opioid tolerance in forensic postmortem cases., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Tea is a recommended way of administration of prescribed cannabis plant products in Denmark. We aimed to investigate the cannabinoid and terpene doses contained in different teas. We analysed tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), and terpene concentrations in three repeated preparations of each type of tea, and in plant material. In standard tea, concentrations of THC were [median (min-max)] 9.5 (2.3-15), 19 (13-34), and 36 (26-57) μg/mL for products with a labelled content of 6.3%, 14%, and 22% total THC (THC + THCA), respectively. The CBD concentration in tea from a product labelled with 8% total CBD (CBD + CBDA) was 7.5 (1.9-10) μg/mL. Based on this, the recommended starting amount of 0.2 L of the different teas would contain between 0.46 and 11.3 mg THC, and 0.38 to 2.0 mg CBD. Adding creamer before, but not after boiling, increased the THC and CBD concentration 2.3-4.4 and 2.1-fold, respectively. Terpenes were detected in plant material, but not in tea. The study elucidates THC and CBD doses in different teas, which may assist the clinician's choice of cannabis product. Moreover, it underscores the need for caution as administration as tea can result in exposure to different doses, even when the same cannabis product is used., (© 2024 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Inter-individual variability in drug response pose significant challenges to treatment with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC). TKIs meet traditional criteria for using therapeutic drug monitoring (TDM), but research is still limited. Understanding the role of TDM in individualizing treatment strategies could help optimize treatment. Here we review the state of knowledge of TDM for TKIs in mRCC treatment. A comprehensive literature review of original research studies focusing on TDM of TKIs in mRCC treatment, clinical in vivo studies reporting on pharmacokinetics-pharmacodynamics, therapeutic ranges, drug concentrations, dose adjustments, clinical outcomes, or other relevant aspects related to TDM. We reviewed studies involving human subjects published in peer-reviewed journals. A narrative synthesis approach was employed to summarize the findings. Key themes and trends related to TDM of TKIs in mRCC treatment were identified and synthesized to provide a comprehensive overview of the current state of knowledge. Our search yielded 25 articles. Most were observational. The most consistently reported association between plasma concentration and effect was pazopanib Ctrough >20 µg/mL, but this concentration was not significant across all studies. We found inconsistent evidence for sunitinib and cabozantinib. For axitinib, we found a clear exposure-response relationship, but research was too diverse to conclude on a therapeutic window to use for TDM. We found much heterogeneity between recommended time of measurement (minimum plasma concentration [C min ], maximal plasma concentration [C max ], area under the curve [AUC]) and large variation in plasma concentration associated with clinical outcomes, which makes it difficult to recommend specific concentration intervals based on 1 or more of these measurements. Results were more consistent with TKIs continuously administered. Further research is needed to elucidate the long-term impact of TDM to possibly establish standardized therapeutic intervals. Prospective studies are suggested. The application of TDM in TKI-combination therapy is warranted in future research., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The objective was to assess the diagnostic accuracy of an enhanced autopsy triage (EA-Triage) setup consisting of postmortem computed tomography (PMCT), simulated quick toxicological analysis (sQTA), external examination, and case information in determining cause of death (COD) in persons with past or current use of illegal drugs (drug-related deaths). Information on drug-related deaths selected for medico-legal autopsy in 2020-2021 at the Department of Forensic Medicine, Aarhus University, Denmark, was analyzed retrospectively. The included cases underwent conventional autopsy, PMCT, and systematic toxicological analysis. A board-certified forensic pathologist, who was blinded to the internal examination and COD from the medico-legal autopsy, determined COD based on the EA-Triage setup. 154 cases with a median age of 40.6 years (range 17-70 years, 82% males) were included. The COD determined by medico-legal autopsy and that determined by EA-Triage matched in 113 cases (73%), including those with an unknown COD. EA-Triage and medico-legal autopsy determined unknown COD in 45 (29%) and 5 cases (3%), respectively. Excluding cases with an unknown COD, EA-Triage predicted COD in 109 cases (71%); of those, 72 (66%) had no unexplained case circumstances or suspicion of a criminal act. In these 72 cases, the CODs determined by EA-Triage and medico-legal autopsy matched in 71 cases (99%), and the sensitivity and specificity for detecting lethal intoxication were 100% and 90%, respectively. EA-Triage showed strong diagnostic accuracy for determining COD in drug-related deaths. This method may be suitable for enhancing preautopsy triage and guiding police investigations at an early stage., (© 2024. The Author(s).)

Introduction: Fatal opioid poisoning is a growing global issue. This study aims to describe circumstances surrounding fatal opioid poisonings by examining death scenes, demographics, and information from bystanders with the goal of informing prevention efforts., Methods: We extracted data from the autopsy reports of 327 forensic autopsy cases with fatal poisoning involving methadone and/or morphine from 2013-2020., Results: Fatal opioid poisonings occurred in both rural and urban areas. Death scene was the decedent's own home and a relative's or friend's home in 62% and 21%, respectively. The decedent died alone in 64% of the cases while other people were staying at the same address while death occurred in 30%. Decedents aged 15-34 years were more likely to die with other people staying at the same address than persons aged > 44 years (OR±SD: 2.3 ± 0.9, p = 0.005), and had lower postmortem blood methadone concentrations compared to persons > 34 years (Median [interquartile range]: 0.36 [0.23-0.62] vs 0.63 [0.28-1.2] mg/kg, p = 0.002). Female sex was more prevalent, and persons using illegal drugs were less prevalent in decedents aged > 44 years compared to those with age 15-44 years (29% vs 20%, p = 0.05% and 67% vs 89%, p < 0.001, respectively). Other psychoactive drugs were detected in 97% of decedents, mainly benzodiazepines (80%)., Conclusions: Preventive strategies based on our findings include the need for harm reduction initiatives in both urban and rural areas, recognizing symptoms of fatal poisoning, and awareness of low tolerance among younger age groups. Urgent attention should be given to avoiding opioid use alone, particularly among older individuals, including women using prescribed opioids. Conveying the risks of polydrug use to all age groups is essential, especially co-use of sedative drugs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JHT is affiliated with Antidote Danmark which is a non-profit organization that promotes harm reduction initiatives including distribution of take-home Naloxone. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Changes in pharmacokinetics and endogenous metabolites may underlie additive biological effects of concomitant use of antipsychotics and opioids. In this study, we employed untargeted metabolomics analysis and targeted analysis to examine the changes in drug metabolites and endogenous metabolites in the prefrontal cortex (PFC), midbrain, and blood of rats following acute co-administration of quetiapine and methadone. Rats were divided into four groups and received cumulative increasing doses of quetiapine (QTP), methadone (MTD), quetiapine + methadone (QTP + MTD), or vehicle (control). All samples were analyzed using liquid chromatography-mass spectrometry (LC-MS). Our findings revealed increased levels of the quetiapine metabolites: Norquetiapine, O-dealkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide, in the blood and brain when methadone was present. Our study also demonstrated a decrease in methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the rat brain when quetiapine was present. Despite these findings, there were only small differences in the levels of 225-296 measured endogenous metabolites due to co-administration compared to single administrations. For example, N-methylglutamic acid, glutaric acid, p-hydroxyphenyllactic acid, and corticosterone levels were significantly decreased in the brain of rats treated with both compounds. Accumulation of serotonin in the midbrain was additionally observed in the MTD group, but not in the QTP + MTD group. In conclusion, this study in rats suggests a few but important additive metabolic effects when quetiapine and methadone are co-administered., (© 2023. The Author(s).)

Fatal poisonings where both methadone and quetiapine are detected post-mortem occurs frequently in legal autopsy cases. It is unclear whether quetiapine increases the risk of fatal methadone poisoning or if it is merely detected due to widespread use. We hypothesized that methadone and quetiapine would have additive toxic effects on respiratory rate, blood pressure, and the QTc-interval. To investigate this hypothesis, we used telemetry implants for measurements of respiratory rate, haemodynamic variables, the velocity of blood pressure changes, temperature, and movement in conscious, freely moving male Wistar rats aged 12-13 weeks. The combined effects of three accumulative i.p. doses of methadone (2.5, 10, 15 mg/kg) and quetiapine (3, 10, 30 mg/kg) were compared to rats treated with the same doses of each drug alone, and a vehicle-treated group in a randomized investigator blinded study. No additive effects of quetiapine and methadone on respiratory rate, haemodynamic variables, or movement were observed. However, body temperature was significantly lower by approximately 1.5°C on average in the group treated with both methadone and quetiapine (15 + 30 mg/kg) compared to the other groups. This indicates a synergistic effect of quetiapine and methadone on thermoregulation, which may increase the risk of fatal poisoning. We suggest studying this finding further in human settings., (© 2023 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Opioid use disorders can be treated with psychosocial interventions which aim to increase quality of life and minimize problems maintaining drug use. In addition, pharmacological treatment with opioid maintenance therapy (OMT) can help minimize morbidity and mortality. The principle for OMT is substituting to another opioid with a more favourable pharmacological profile, primarily buprenorphine or methadone. The first choice is buprenorphine in combination with naloxone. The aim of this review is to summarize current principles for handling patients in OMT.

Introduction: Paracetamol poisoning is a frequent cause of hospitalization in Denmark. On 30 September 2013, the Danish authorities restricted packages available without a prescription in pharmacy outlets to contain a maximum of 10 g of paracetamol. We aimed to investigate the effects of this regulation., Methods: This was a cross-sectional study of two groups of patients admitted consecutively to a Danish University Hospital due to poisoning with paracetamol in 365 days in 2012-13 before 30 September 2013, and a corresponding 365-day period in 2017-18. Data were extracted from patient records., Results: In 2012-2013 and 2017-18, 156 and 92 admissions in 127 and 78 unique patients, respectively, were identified. Ingestion of more than 20 g paracetamol occurred in a significantly higher proportion of cases in 2012-13 compared to 2017-18 (29% vs 13%, P  < 0.01). In accordance, there were no cases of international normalized ratio >1.5 or alanine aminotransferase activity >1000 U/L in the post-legislation period, and seven and five cases in the pre-legislation period, respectively. Females accounted for 80% and 78% of patients in the two periods, respectively, and were considerably younger than males (median [interquartile range]: 22 [17-40] vs. 47 [30-56], P  < 0.01 in 2012-13, and 23 [18-46] vs. 43 [27-49] years, P  = 0.02 in 2017-18). Furthermore, in 2012-13, intentional poisonings occurred in a higher proportion of females than males 2012-13 (97% vs 85%, P  < 0.01)., Conclusions: The present study demonstrated a lower number of paracetamol poisonings, a decreased proportion of poisonings involving ingestion of more than 20 g of paracetamol, and a lower occurrence of hepatotoxicity after the regulation. However, circumstances other than pack size restrictions, such as increased public awareness of the danger of paracetamol poisonings, may affect these associations. Furthermore, the study showed that females and males constitute two distinct groups in terms of age and intentional poisoning.

Lisdexamfetamine (LDX) is a prodrug that is enzymatically converted into dextroamphetamine (d-AMP), a central nervous system stimulant. The stability of LDX in sampled whole blood is an important issue that may be crucial in the assessment of impaired driving caused by d-AMP. This study investigated the stability of LDX in whole blood collected in two different tubes containing a fluoride oxalate (FX) mixture and a fluoride citrate (FC) mixture. Without additives, LDX was unstable. LDX was also unstable in FX blood stored at ambient temperature or 4°C. After 3 days of storage at ambient temperature, an initial LDX concentration of 47 ± 1 ng/g (mean ± SD) was no longer detectable in the samples (n = 3). Instead, 19 ± 0.6 ng/g d-AMP was formed. The stability was improved at 4°C. After 7 days of storage at 4°C, 88 ± 5% of an initial LDX concentration of 50 ± 0.4 ng/g was recovered and 3.8 ± 0.3 ng/g d-AMP was formed. The stability of LDX was greater in FC blood than in FX blood; 79 ± 10% and 93 ± 4% of initial LDX concentrations of 48 ± 2 and 51 ± 0.5 ng/g were recovered from FC blood after 7 days of storage at ambient temperature and 4°C, respectively, and the corresponding formation of d-AMP was 5.8 ± 0.6 and 0.5 ± 0.3 ng/g, respectively. When FX and FC blood were stored at -20°C or -80°C, no detectable degradation of LDX or formation of d-AMP was observed after 3 weeks of storage., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Information regarding deaths caused by poisoning or adverse effects of medication in Danish persons not using illicit narcotic drugs (PNUIDs) is sparse. To characterize aetiology, demographics, and death scene, we reviewed all legal autopsies performed at Aarhus University from 2017 to 2019 and isolated 96 deaths caused by medications in PNUIDs. Suicides caused by medication overdose accounted for 38%. Opioids and psychotropic medications were the main cause of death in 48% and 35% of the 96 cases, respectively. Morphine, tramadol, and quetiapine were the most commonly involved individual medications. A single medication caused death in 50% of cases, and multiple substances were involved in 50%. The median total number [interquartile range] of detected medications was 5 [4-6], with a higher number in females (5 [4-7]) than males (4 [2-5]), p = 0.009. Median age was 51 [42.5-61.5] years, and 57% were female. Scene of death most frequently involved a body on a bed or couch in the decedent's own home (72%). In conclusion, opioids and psychotropic medications dominated by morphine, tramadol and quetiapine most frequently caused medication-related deaths in PNUIDs. Monitoring this type of death may yield important knowledge to direct prophylactic initiatives regarding medication use and prescription., (© 2022 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Introduction: The high prevalence of chronic medical conditions among older adults leads to an increased use of prescription medications and a heightened risk of polypharmacy, raising the risk of falls and fractures. Psychotropic medications influence balance, and therefore our aim was to describe the use of psychotropic medications and the association with polypharmacy in elderly patients with a hip fracture., Methods: A retrospective study of 200 patients aged 65 years or more admitted consecutively with a hip fracture., Results: In total, 98 of the 200 patients used psychotropic medications. These 98 patients used a higher number of drugs at the time of admission (an average of eight (6-11) versus six (3-10), p less-than0.001), had a higher risk of using five or more medications (odds ratio (OR) = 5.9; 95% confidence interval (CI): 2.75-12.7; p less-than 0.001) and a higher risk of using ten or more medications (OR = 1.9; 95% CI: 1.05-3.5; p = 0.03). Furthermore, they were more likely to use analgesics (65.3% versus 48.0%; p = 0.01) and medications targeting the gastrointestinal tract (59.1% versus 40.2%; p = 0.01)., Conclusions: Psychotropic medication use was frequent in elderly patients with a hip fracture and strongly associated with polypharmacy. Psychotropic medications may potentially be a trigger to perform medication review in elderly patients to prevent re-occurrence hip fractures., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Fatal opioid poisonings often involve methadone or morphine. This study aimed to elucidate if quetiapine, a widely used sedative antipsychotic medication, may increase the risk of fatal opioid poisoning by additive inhibitory effects on the central nervous system. We used data from 323 cases of fatal methadone or/and morphine poisonings autopsied from 2013 to 2020, a survey of 34 drug users, and performed blinded placebo-controlled studies in 75 Flinders Resistant Line rats receiving three cumulative intraperitoneal doses of vehicle, methadone (2.5, 10 and 15 mg/kg), morphine (3.75, 15 and 22.5 mg/kg), quetiapine (3, 10 and 30 mg/kg) or quetiapine combined with methadone or morphine. Quetiapine was detected in 20.4% of fatal opioid poisonings with a significantly increased frequency over time, primarily in low or therapeutic concentrations, and was not associated with methadone or morphine concentrations. Use of quetiapine, most commonly in low-to-moderate doses to obtain a sleep-inducing or tranquillizing effect, was reported by 67.6% of survey respondents. In the animal studies, a significant impairment of sedation score, performance on the rotarod and open field mobility was observed in all treatment groups compared with vehicle. However, the effect of quetiapine plus the opioid was not significantly different from that of the opioid alone. Thus, no additive sedative effects were observed in rats. Our results suggest that quetiapine is more often an innocent bystander than a contributor to fatal opioid poisoning. However, the combined effects on other parameters, including blood pressure, cardiac rhythm and respiratory rate, need investigation., (© 2022 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Purpose: The superior and inferior tarsal muscles are sympathetically innervated smooth muscles. Long-term diabetes often leads to microvascular complications, such as, retinopathy and autonomic neuropathy. We hypothesized that diabetes induces (1) sympathetic paresis in the superior and inferior tarsal muscles and that this measure is associated with (2) the severity of diabetic retinopathy, (3) the duration of diabetes, and (4) autonomic function. In addition, association between the severity of retinopathy and autonomic function was investigated., Methods: Forty-eight participants with long-term type 1 diabetes and confirmed distal symmetrical polyneuropathy were included. Palpebral fissure heights were measured bilaterally in response to topically applied 10% phenylephrine to the right eye. The presence of proliferative diabetic retinopathy (PDR) or nonproliferative diabetic retinopathy and disease duration were denoted. Time and frequency derived heart rate variability parameters obtained from 24-hour continuous electrocardiography were recorded., Results: The difference in palpebral fissure heights between phenylephrine treated and untreated eyes (∆PFH) was 1.02 mm ± 0.29 (P = 0.001). The ∆PFH was significantly lower in the PDR group (0.41 mm ± 0.43 vs. 1.27 mm ± 1.0), F(1,35) = 5.26, P = 0.011. The ∆PFH was lower with increasing diabetes duration, r(37) = -0.612, P = 0.000. Further, the ∆PFH was lower with diminished autonomic function assessed as total frequency power in electrocardiogram (r = 0.417, P = 0.014), and sympathetic measures of very low (r = 0.437, P = 0.010) and low frequency power (r = 0.384, P = 0.025)., Conclusions: The ∆PFH is a simple ambulatory sympathetic measure, which was associated with the presence of PDR, disease duration, and autonomic function. Consequently, ∆PFH could potentially be an inexpensive and sensitive clinical indicator of autonomic dysfunction.

GHB is an endogenous short-chain organic acid presumably also widely applied as a rape and knock out drug in cases of drug-facilitated crimes or sexual assaults (DFSA). Due to the endogenous nature of GHB and its fast metabolism in vivo , the detection window of exogenous GHB is however narrow, making it challenging to prove use of GHB in DFSA cases. Alternative markers of GHB intake have recently appeared though none has hitherto been validated for forensic use. UHPLC-HRMS based screening of blood samples for drugs of abuse is routinely performed in several forensic laboratories which leaves an enormous amount of unexploited data. Recently we devised a novel metabolomics approach to use archived data from such routine screenings for elucidating both direct metabolites from exogenous compounds, but potentially also regulation of endogenous metabolism and metabolites. In this paper we used UHPLC-HRMS data acquired over a 6-year period from whole blood analysis of 51 drivers driving under the influence of GHB as well as a matched control group. The data were analyzed using a metabolomics approach applying a range of advanced analytical methods such as OPLS-DA, LASSO, random forest, and Pearson correlation to examine the data in depth and demonstrate the feasibility and potential power of the approach. This was done by initially detecting a range of potential biomarkers of GHB consumption, some that previously have been found in controlled GHB studies, as well as several new potential markers not hitherto known. Furthermore, we investigate the impact of GHB intake on human metabolism. In aggregate, we demonstrate the feasibility to extract meaningful information from archived data here exemplified using GHB cases. Hereby we hope to pave the way for more general use of the principle to elucidate human metabolites of e.g. new legal or illegal drugs as well as for applications in more global and large scale metabolomics studies in the future., 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 © 2022 Wang, Nielsen, Frisch, Lassen, Nielsen, Andersen, Villesen, Andreasen, Hasselstrøm and Johannsen.)

Knowledge about current trends and epidemiology in poisonings is important to maintain quality in diagnostics, treatment and prevention. We performed a cross-sectional study of all cases (n = 261) admitted with drug poisoning to Aalborg University Hospital during 1 year in 2017-2018. Median age was 30 (22-49) years, and 58% were female. Fifty percent were suicide attempts. In most cases, involved drugs were identified by history taking; blood analysis barely revealed any additional paracetamol and salicylicate poisonings. Drugs prescribed to the patient or available over the counter were involved in nearly two thirds of cases. Weak analgesics dominated by paracetamol (n = 91, 35%) was the most frequently involved group of drugs followed by opioids and benzodiazepines. Gender differences were observed with respect to involvement of weak analgesics and central stimulants. A higher prevalence of unidentified involved drugs was observed in 26 cases (10%) in which the length of admission exceeded 2 days and/or intensive care was needed. No deaths, cardiac arrhythmias or physical complications occurred. Thus, current handling of the acute poisoning seems effective in most cases. However, a more tailored use of blood analyses including a toxicological screen in selected cases may represent an opportunity for improvement., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Cocaine-related emergency department admissions are increasing, and cocaine seizures are at an all-time high in Europe. Our aim was to investigate the trends in purity and adulterants over time in cocaine available to cocaine users at street level in Denmark. We used a representative sample of cocaine seized at street level and analyzed by the national departments of forensic medicine between 2006 and 2019 (n = 1460). Latent profile analysis was used to classify the samples based on cocaine, levamisole, and phenacetin content. Low purity cocaine comprised most of the cocaine seizures in early years, but its share began to decline in 2013, and from 2016 to 2019, the high purity profile was dominant. While the total number of samples containing adulterants decreased, levamisole remained a common and dangerous adulterant. The findings underline the need to inform the public, medical doctors, and service providers for people with drug use disorders about the higher potency of street cocaine., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Medication-induced prolongation of the QT-interval (miQTP) can lead to cardiac arrhythmia. Our aim was to investigate the prevalence of forensic autopsy cases where fatal cardiac arrhythmia related to treatment with QT-prolonging medications (QT-PMs) could be suspected. We performed a cross-sectional study of 741 forensic autopsies undertaken at our institution in non-drug addicts aged 15 years or above from 2017 to 2019. We defined a high risk of miQTP by one detected QT-PM in a concentration above therapeutic level, or two or more detected QT-PMs in post mortem blood. We reviewed the autopsy reports from cases with a high miQTP-risk to identify cases with no other apparent cause of death. We discarded suicides and cases with lethal levels of QT-PMs. We identified 167 cases (22.5%) with high risk of miQTP, and discarded 36 suicides (4.9%) and 7 (0.9%) with lethal levels of QT-PMs. Apart from a high risk of miQTP, no other apparent explanation of the cause of death was present in seven (0.9%). In 18 cases (2.4%) with high miQTP-risk, the cause of death was primarily attributed to cardiac changes other than acute cardiovascular events. In conclusion, 22.5% had a high risk of miQTP, and fatal cardiac arrhythmia related to treatment with QT-PMs could be suspected in 0.9%. However, a genetic pro-arrhythmic background could not be excluded in our study. Furthermore, it is possible that QT-PMs could have played a role in some of the 2.4% of cases where the cause of death was mainly attributed to cardiac changes and the risk of miQTP was high., Competing Interests: Declarations of interest The authors have no conflicts of interest to declare., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

This case report describes a 57-year-old male with symptoms of tardive akathisia after long-term metoclopramide treatment. As metoclopramide is a dopamine receptor antagonist, it has the potential to cause drug-induced movement disorders, including akathisia, which is characterised by an inner restlessness resulting in a need for constant movement. Tardive akathisia, in contrast to acute akathisia, evolves after prolonged exposure to the triggering medication and can be a permanent condition. Treatment duration of metoclopramide should be restricted, and awareness of neurological side effects is important.

Opioid poisoning is a frequent cause of death in drug addicts and occurs with opioid treatment. Quetiapine is often found in forensic autopsies and may increase the risk of fatal opioid poisoning by enhancing sedation, respiratory depression, hypotension and QT prolongation. We systematically searched for studies of acute toxicity of quetiapine or other antipsychotics combined with morphine or methadone. Case reports describing toxicity of quetiapine combined with morphine or methadone were also included. We retrieved one human study that observed pharmacokinetic interaction between quetiapine and methadone, and 16 other human studies. Fourteen investigated the combination of droperidol and morphine in treatment doses, and some indicated an additive sedative effect. Five animal studies with acepromazine in combination with morphine or methadone were located and indicated an additive effect on sedation and hypotension. Six forensic case reports in which death could have been caused solely by quetiapine, the opioid, or other drugs were found. Thus, acute toxicity of quetiapine combined with morphine or methadone has not been studied. Because of quetiapine's effects on alpha-adrenoceptors, muscarinic and histamine receptors, human ether-a-go-go-channels and methadone kinetics, we suggest further research to clarify if the indicated additive effects of opioids and droperidol or acepromazine are also true for quetiapine., (© 2020 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Introduction: Pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary arteries, leading to right ventricular hypertrophy and failure. We have previously found upregulation of transglutaminase 2 (TG2) in the right ventricle of chronic hypoxic rats. The hypothesis of the present study was that treatment with the transglutaminase inhibitor, cystamine, would inhibit the development of pulmonary arterial remodeling, pulmonary hypertension, and right ventricular hypertrophy., Methods: Effect of cystamine on transamidase activity was investigated in tissue homogenates. Wistar rats were exposed to chronic hypoxia and treated with vehicle, cystamine (40 mg/kg/day in mini-osmotic pumps), sildenafil (25 mg/kg/day), or the combination for 2 weeks., Results: Cystamine concentration-dependently inhibited TG2 transamidase activity in liver and lung homogenates. In contrast to cystamine, sildenafil reduced right ventricular systolic pressure and hypertrophy and decreased pulmonary vascular resistance and muscularization in chronic hypoxic rats. Fibrosis in the lung tissue decreased in chronic hypoxic rats treated with cystamine. TG2 expression was similar in the right ventricle and lung tissue of drug and vehicle-treated hypoxic rats., Discussion/conclusions: Cystamine inhibited TG2 transamidase activity, but cystamine failed to prevent pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial muscularization in the chronic hypoxic rat., (© 2021 S. Karger AG, Basel.)

Introduction: Knowledge of trends of illegal drug use is vital for planning initiatives to reduce accidents and deaths among drug users. The aim of this study was to describe the cause of death, abuse pattern and geographic differences in fatal poisonings among drug users in Denmark in 2017., Methods: All fatal poisonings among drug users examined at the three institutes of forensic medicine in Denmark in 2017 were included in the study., Results: Overall, fatal poisonings declined from a maximum of 226 in 2007 to 162 in 2017. Methadone (52%) was the most common cause of death, followed by heroin/morphine (25%). A marked increase in deaths was due to stimulants (13%), especially cocaine. The abuse pattern has changed since 2012. Methadone remained the most frequently detected drug, but clonazepam and cocaine surpassed heroin/morphine, diazepam and tetrahydrocannabinol as the second-most frequently detected drugs. Ketobemidone had disappeared, whereas buprenorphine, oxycodone, fentanyl, pregabalin and gabapentin had increased. Antidepressants/antipsychotics were detected in half (47%) of the cases. Cocaine was more frequent in the areas covered by Copenhagen and Aarhus, whereas heroin/morphine was most frequently detected in the area covered by Odense. Amphetamine was more frequent in the Aarhus area., Conclusions: Methadone and heroin/morphine still account for most fatal poisonings. However, deaths due to stimulants, especially cocaine, have increased. The abuse pattern has changed and geographical differences have emerged., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

This study is the seventh report on fatal poisonings among drug addicts in the Nordic countries. In this report, we analyse data from the five Nordic countries: Denmark, Finland, Iceland, Norway and Sweden. Data on gender, number of deaths, places of deaths, age, main intoxicants and substances detected in blood were recorded to obtain national and comparable Nordic data, and to allow comparison with earlier studies conducted in 1984, 1991, 1997, 2002, 2007 and 2012. The death rate (number of deaths per 100,000 inhabitants) was highest in Iceland (6.58) followed closely by Sweden (6.46) and then lowest in Denmark (4.29). The death rate increased in Finland (5.84), Iceland and Sweden and decreased in Denmark compared to earlier studies. The death rate in Norway, which has decreased since 2002, has stabilised around 5.7 as of 2017. Women accounted for 7-23% of the fatal poisonings. The percentage was lowest in Iceland and highest in Finland and Norway. The age range was 14-70 years. The median age (41 years) was highest in Denmark and Norway. The other countries had a median age between 33 and 35 years. Opioids were the main cause of death. Methadone remained the main intoxicant in Denmark, while heroin/morphine was still the main intoxicant in Norway, as was buprenorphine in Finland. However, the picture has changed in Sweden compared to 2012, where heroin/morphine caused most deaths in 2017. Sweden also experienced the highest number of deaths from fentanyl analogues (67 deaths) and buprenorphine (61 deaths). Deaths from fentanyl analogues also occurred in Denmark, Finland and Norway, but to a smaller extent. Over the years, the proportion of opioid deaths has decreased in all countries except Sweden, which has experienced an increase. This decline has been replaced by deaths from CNS stimulants like cocaine, amphetamine and methylenedioxymethamphetamine (MDMA). Cocaine deaths have occurred in all countries but most frequently in Denmark. MDMA deaths have increased in all countries but mostly in Finland. Poly-drug use was widespread, as seen in the earlier studies. The median number of detected drugs per case varied from 4-6. Heroin/morphine, methadone, buprenorphine, cocaine, amphetamine, methamphetamine, MDMA, tetrahydrocannabinol (THC) and benzodiazepines were frequently detected. Pregabalin and gabapentin were detected in all countries, especially pregabalin, which was detected in 42% of the Finnish cases. New psychoactive substances (NPS) occurred in all countries except Iceland., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Patients suffering from fibrotic interstitial lung diseases (fILD) have a poor prognosis and a high symptom burden. Palliative treatment includes relief of symptoms such as breathlessness. There is no evidence-based treatment for chronic breathlessness but opioids are often used despite concerns due to the hypothetical risk of respiratory depression. This study investigated the effect of oral morphine drops in patients with fILD on chronic breathlessness and safety., Methods: In a double-blinded placebo-controlled study, 36 patients with fILD were randomised to either four daily doses of 5 mg of oral morphine drops or placebo for 1 week. Endpoints and safety parameters were obtained at baseline, at follow-up after 1 h and 1 week., Results: The primary endpoint, the visual analogue score (VAS) of dyspnea was reduced by 1.1 ± 0.33 cm in the morphine group at follow-up compared to baseline (P < 0.01), whereas the reduction was 0.35 ± 0.47 cm in the placebo group. However, the difference between the two groups was not statistically significant (p = 0.2). Oral morphine drops did not affect respiratory frequency, pulse rate, blood pressure, peripheral saturation or the 6-min walk test. More patients treated with morphine reported constipation, nausea and confusion., Conclusion: Oral administration of morphine drops, 20 mg a day, in patients with fILD did not significantly reduce dyspnea VAS score during 1 week compared to placebo. Oral morphine did not induce respiratory depression, but was related to an increased risk of constipation, nausea and confusion., Trial Registration: The trial is registered in clinicaltrials.gov (Identifier: NCT02622022 ). Registered 4 December 2015.

Macular oedema is a known side effect to fingolimod, but changes in specific areas of the retina are only sparsely described. Our aim was to investigate the prevalence of macular oedema and characterize macular changes after initiation of fingolimod based on routine ophthalmological examinations in all consecutive patients treated at our hospital. We evaluated macular thickness change from baseline to 3-4 months after initiation of treatment. Central retinal thickness, total macular volume, total macular thickness, average thickness and inner-/outer macular thickness were automatically measured using optical coherence tomography (OCT). A total of 190 eyes completed the study, and none of those developed visible macular oedema. All macular areas showed a small, but statistically significant increase in thickness. Total macular volume increased by a mean of 0.05 mm 3 (P = <.001). Mean best-corrected visual acuity only changed by .03 (P = .074). We observed a minimal change in macular thickness and no clinically relevant affection on visual acuity after 3-4 months of fingolimod treatment. Thus, our results do not underpin the need for routine screening for macular oedema in asymptomatic MS patients without diabetes or uveitis receiving 0.5 mg fingolimod daily., (© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

It is well-known that use of continuous systemic corticosteroids (SG) affects bone metabolism, bone mineral density (BMD), and ultimately increases the risk of osteoporosis. In patients with asthma, on the other hand, the effects of long-term high-dose inhaled corticosteroids (ICS) on BMD and risk of osteoporotic fractures is controversial. The reasons for this inconsistency could be explained by the fact that only few long-term studies investigating the effect of ICS in patients with asthma exist. The studies are characterized by different study designs and duration of ICS exposure, small study populations, and differences between the used ICS. The aim of this article is to unravel which factors, if any, that contribute to an increased risk of osteoporosis in patients with asthma and to summarize the evidence regarding adverse effects of ICS on bone metabolism, BMD and osteoporotic fractures in patients with asthma., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Hip fractures constitute a major health problem in elderly people and are often fall-related. Several factors can contribute to a fall episode leading to hip fracture, including fall-risk-increasing drugs (FRIDs), which are often used by elderly people. We aimed to investigate the prevalence of medication-related falls and to assess the role of FRIDs and potentially inappropriate medications (PIMs) in a population of elderly patients hospitalized for a hip fracture., Methods: We reviewed the patient records of 200 consecutive patients, aged ≥65 years, who were admitted for a hip fracture and evaluated whether medications were likely to have contributed to the fall episode. PIMs were identified using the Screening Tool of Older Persons' Prescriptions version 2 (STOPP) and by evaluating indications, contra-indications and interactions of the prescribed medications for each patient., Results: FRIDs were used by 175 patients (87.5%). Medications were considered a likely contributor to the fall in 82 patients (41%). These were most often psychotropic medications alone or in combination with antihypertensives and/or diuretics. The 82 patients with suspected medication-related falls used more medications, FRIDs and PIMs than the rest of the patients, and in 74 (90%) of the 82 patients, at least one medication considered to be a contributor to the fall was also a PIM., Conclusions: The prevalence of suspected medication-related falls was 41%. It seems likely that a medication review could have reduced, though not eliminated, the risk of falling in this group of patients.

Aims: Emerging evidence shows, that distal symmetric peripheral neuropathy (DSPN) also involves alterations in the central nervous system. Hence, the aims were to investigate brain metabolites in white matter of adults with diabetes and DSPN, and to compare any cerebral disparities with peripheral nerve characteristics., Methods: In type 1 diabetes, brain metabolites of 47 adults with confirmed DSPN were compared with 28 matched healthy controls using proton magnetic resonance spectroscopy (H-MRS) in the parietal region including the sensorimotor fiber tracts., Results: Adults with diabetes had 9.3% lower ratio of N-acetylaspartate/creatine (NAA/cre) in comparison to healthy (p < 0.001). Lower NAA/cre was associated with lower sural (p = 0.01) and tibial (p = 0.04) nerve amplitudes, longer diabetes duration (p = 0.03) and higher age (p = 0.03). In addition, NAA/cre was significantly lower in the subgroup with proliferative retinopathy as compared to the subgroup with non-proliferative retinopathy (p = 0.02)., Conclusions: The association to peripheral nerve dysfunction, indicates concomitant presence of DSPN and central neuropathies, supporting the increasing recognition of diabetic neuropathy being, at least partly, a disease leading to polyneuropathy. Decreased NAA, is a potential promising biomarker of central neuronal dysfunction or loss, and thus may be useful to measure progression of neuropathy in diabetes or other neurodegenerative diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Patients with chronic obstructive pulmonary disease (COPD) are at risk of developing osteoporosis, as the COPD in itself as well as continued smoking and treatment with systemic corticosteroid all increase the risk of developing osteoporosis. Other risk factors for osteoporosis are low vitamin D levels, malnutrition and physical inactivity. All patients who have risk factors in the form of severe COPD, and all patients with COPD in active treatment with systemic corticosteroid and/or other risk factors should be examined with a DEXA-scan. Treatment of osteoporosis in patients with COPD does not differ from general recommendations.

Adverse effects can compromise oral voriconazole treatment of pulmonary aspergillosis. Inhaled low-dose voriconazole may be an alternative treatment. In this study, six patients inhaled 40 mg voriconazole b.i.d. for 2 days, and six patients ingested 400 and 200 mg orally b.i.d. on day one and two, respectively. Blood samples were collected after the first inhalation, and bronchial alveolar lavage fluids and blood samples were collected for measurements of voriconazole 12 hr after the last administration. The concentration of voriconazole in epithelial lining fluid (ELF) was calculated by the urea dilution method. Voriconazole concentrations were detectable in plasma 15 min. after inhalation and declined at 30 and 60 min. Twelve hours after the last dose, median (95% CI) plasma voriconazole concentration was 8 (4-26) ng/mL in the inhalation group and 1224 (535-2341) ng/mL in the oral group (p < 0.0001). In ELF, median concentration was 190 (55-318) ng/mL and 8827 (4369-35172) ng/mL, respectively (p < 0.0001). Median ELF/plasma concentration ratio was 21 (6-63) in the inhalation group and 8 (3-20) in the oral group (p = 0.2). In conclusion, voriconazole is rapidly absorbed into the systemic circulation after inhalation. There was a non-significant trend towards a higher ELF/plasma concentration ratio in the inhalation group compared to the oral group., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Purpose: Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease in which optic neuropathy is considered a key feature. Several other manifestations of LHON have been reported; however, only little is known of their incidence and the life expectancy in LHON patients., Methods: This study, based on Danish nationwide health registries, included 141 patients diagnosed with LHON and 297 unaffected family members in the maternal line. The incidence of comorbidities and mortality for patients with LHON and unaffected family members was compared with that in the general population., Results: Having LHON was associated with an almost 2-fold risk of mortality with a rate ratio (RR) of 1.95 (95% confidence interval [CI]: 1.47-2.59; P < 0.001). The incidence of several diseases was increased for LHON patients, but not for family members. The incidence of stroke was 5.73 per 1000 patient-years for LHON patients compared to 2.33 for the general population, and the RR was 2.38 (95% CI: 1.58-3.58; P < 0.001). The incidence of demyelinating disorders was 2.24 compared to 0.21 for the general population; RR was 12.89 (95% CI: 6.70-24.77; P < 0.001). A 4-fold risk of dementia was seen for LHON patients (RR: 4.26, 95% CI: 1.91-9.48; P < 0.001), incidence 1.45 for LHON and 0.37 for the general population. Moreover, LHON patients had an increased risk of epilepsy, atherosclerosis, nerve symptoms, neuropathy, and alcohol-related disorders., Conclusions: The manifestation of LHON was associated with increased mortality and increased incidence of several disorders including stroke, demyelinating disorder, dementia, and epilepsy.

Purpose: To address the use of and knowledge about skills assessment and competency-based training in cataract surgery in European Board of Ophthalmology (EBO) member countries., Methods: A survey was emailed directly to all directors of the European societies in ophthalmology. The survey included queries about criteria to undergo training in cataract surgery, regulation of education in cataract surgery, and skills assessment and training methods. In addition, all Danish Eye Departments were further asked to what extent they find assessment tools useful, if competency-based training in cataract surgery would be an improvement, and if an assessment tool would be considered for use in future training of cataract surgeons., Results: Training in cataract surgery in EBO countries is very diverse; although some EBO countries consider it mandatory in residency, most do not. In EBO countries where training is mandatory and regulated by the local health authority, the use of skills assessment tools and competency-based education are more prevalent (e.g., U.K., Ireland, Switzerland, and the Netherlands). In Denmark, training in cataract surgery is not mandatory, and none of the eye departments used assessment scores to evaluate their trainees; 63% did not believe that using assessment tools would improve the outcome of surgical training, and less than one-third would consider frequent use of assessment tools in the future., Conclusion: General unawareness and scepticism toward objective structured assessment of technical skills and a considerable heterogeneity in concept and organization of training in cataract surgery across EBO countries is an issue to address., (Copyright © 2016 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Background: Idiopathic pulmonary fibrosis (IPF) is the most common among the idiopathic interstitial pneumonias and has the worst prognosis, with a median survival of 3-5 years. The most common symptom in IPF is dyspnea, impacting on the patient's quality of life and life expectancy. Morphine in the treatment of dyspnea has been investigated but with conflicting results. This review aims to clarify the role of opioids in the treatment of dyspnea in patients with IPF., Methods: A literature search was performed using the MeSH and PubMed databases. As only very few studies included patients with IPF, studies conducted primarily with patients with chronic obstructive pulmonary disease were also included. In total, 14 articles were found., Results: Seven studies reported use of systemic morphine and seven studies of inhaled morphine. Five of the seven studies investigating systemic administration detected an improvement in either dyspnea or exercise capacity, whereas no beneficial effect on dyspnea was detected in any study using inhaled morphine. No severe adverse effects such as respiratory depression were reported in any study, although constipation was reported as a notable adverse effect., Conclusions: Results were inconsistent, but in some studies systemic morphine administration showed a significant improvement in the dyspnea score on a visual analog scale without observation of severe side effects. Nebulized morphine had no effect on dyspnea.

Traditionally, haloperidol has been the recommended antipsychotic drug for pharmacological treatment of delirium, which is a frequent complication in the critical care setting. Due to a less frequent occurrence of extrapyramidal adverse effects, second-generation antipsychotic drugs have been evaluated. In the present paper we review the current randomized prospective studies of second-generation antipsychotics as treatment for delirium in hospitalized patients and conclude that so far the evidence in favour of these drugs compared with haloperidol is still sparse.

Bleomycin-induced pneumonitis (BIP) is a serious and potentially fatal adverse effect of bleomycin. Currently, BIP is treated on an empirical basis with high dose steroid. Pirfenidone is a new antifibrotic drug, which has been proven beneficial in idiopathic pulmonary fibrosis and is able to inhibit or reverse BIP in animal models. Here, the first two cases of human BIP treated with pirfenidone in addition to steroid therapy are presented. Unfortunately, both patients died, which may be explained by the initiation of therapy at a late stage. Therefore, studies of early or prophylactic treatment with pirfenidone in relation to bleomycin-containing chemotherapy regimens are needed.

The prevalence of obesity increases and is associated with increases in co-morbidities e.g. type 2 diabetes, hyperlipidemia, hypertension, obstructive sleep apnea, heart disease, stroke, asthma, several forms of cancer, depression, and may result in reduction of expected remaining lifespan. We have reviewed the adverse effects on the cardiovascular system of anti-obesity drugs now retracted from the market as well as the cardiovascular profile of current drugs and potential pathways which are considered for treatment of obesity. Fenfluramine, and sibutramine were withdrawn due to increased cardiovascular risk, while an inverse agonist at cannabinoid type 1 (CB1) receptors, rimonobant was withdrawn due to serious psychiatric problems. At present there are only few treatments available including orlistat and, phentermine alone or in combination with topiramate and lorcaserin, although cardiovascular side effects need to be clarified regarding phentermine and lorcaserin. Drugs approved for type 2 diabetes including glucagon like peptide (GLP-1) analogues and metformin also cause moderate weight losses and have a favourable cardiovascular profile, while the anti-obesity potential of nebivolol remains unexplored. Pathways with anti-obesity potential include sirtuin activation, blockade of transient receptor potential (TRPV1) channels, acetyl-CoA carboxylase 1 and 2 inhibitors, uncoupling protein activators, bile acids, crotonins, CB1 antagonists, but the cardiovascular profile remains to be investigated. For type 2 diabetes, new drug classes with possible advantageous cardiovascular profiles, e.g. GLP-1 analogues and sodium-glucose co-transport type 2 inhibitors, are associated with weight loss and are currently being evaluated as anti-obesity drugs.

Traditionally, haloperidol has been the recommended antipsychotic drug for pharmacological treatment of delirium, which is a frequent complication in the critical care setting. Due to a less frequent occurrence of extrapyramidal adverse effects, second-generation antipsychotic drugs have been evaluated. In the present paper we review the current randomized prospective studies of second-generation antipsychotics as treatment for delirium in hospitalized patients and conclude that so far the evidence in favour of these drugs compared with haloperidol is still sparse.

The purpose of the present review is to summarize the current knowledge on PH in relation to COPD and ILD from a clinical perspective with emphasis on diagnosis, biomarkers, prevalence, impact, treatment, and practical implications. PH in COPD and ILD is associated with a poor prognosis, and is considered one of the most frequent types of PH. However, the prevalence of PH among patients with COPD and ILD is not clear. The diagnosis of PH in chronic lung disease is often established by echocardiographic screening, but definitive diagnosis requires right heart catheterization, which is not systematically performed in clinical practice. Given the large number of patients with chronic lung disease, biomarkers to preclude or increase suspicion of PH are needed. NT-proBNP may be used as a rule-out test, but biomarkers with a high specificity for PH are still required. It is not known whether specific treatment with existent drugs effective in pulmonary arterial hypertension (PAH) is beneficial in lung disease related PH. Studies investigating existing PAH drugs in animal models of lung disease related PH have indicated a positive effect, and so have case reports and open label studies. However, treatment with systemically administered pulmonary vasodilators implies the risk of worsening the ventilation-perfusion mismatch in patients with lung disease. Inhaled vasodilators may be better suited for PH in lung disease, but new treatment modalities are also required., (© 2013.)

Background: Pulmonary hypertension (PH) is an important complication to interstitial lung disease (ILD). The aim of the present study was to investigate the relation of NT-proBNP, fibrin D-dimer, troponin-T, uric acid and exhaled nitric oxide (NO) to the presence of PH and mortality in ILD., Methods: In a previously described cohort of 212 ILD patients of whom 29 had PH, levels of the above mentioned biomarkers were analyzed as routine tests., Results: A value of NT-proBNP below 95 ng/l had a negative predictive value for PH of 99% (95% CI: 94-100). Values of troponin-T were higher in patients with PH (median (inter quartile range) = 9 (9-20) vs. 9(9-10) ng/l), and the odds ratio (OR) for PH was increased in patients with abnormal levels of uric acid (OR (95% CI) = 3.1(1.1-8.8)). NT-proBNP and troponin-T values above the 50(th) percentile, and uric acid and fibrin D-dimer values above the 90th percentile were each associated with increased mortality., Conclusions: A value of NT-proBNP below 95 ng/l may be used as a rule-out test for PH in ILD, while an abnormal value of uric acid is a risk factor for PH. NT-proBNP, troponin-T, uric acid and fibrin D-dimer have prognostic value in ILD patients, while exhaled levels of NO do not seem to predict PH or mortality., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Unlabelled: Pulmonary hypertension (PH) worsens the prognosis in chronic obstructive pulmonary disease (COPD). The diagnosis of PH is established by right heart catheterisation (RHC), while echocardiography can be used for screening. We aimed to asses the outcome of echocardiographic screening for PH in a group of stable COPD out-patients, and to evaluate NT-proBNP as a first line screening tool. Criteria for PH on echocardiography were a tricuspid regurgitation pressure gradient > 40 mmHg, a tricuspid annular plane systolic excursion < 1.8 cm or right ventricular dilatation. Positively screened patients were asked to undergo RHC. Results (Mean ± SEM): 16 of 117 patients (14%) had PH on echocardiography. They had a higher mortality (hazard ratio for death: 2.7 ± 1.3, p = 0.037) and lower six minute walk test (224 ± 33 vs. 339 ± 15, p = 0.006). NT-proBNP below 95 ng/l excluded PH on echocardiography with a negative predictive value of 100 (95% CI: 89-100%). RHC was obtained in six patients screened positive. In three of these, PH was not confirmed., Conclusions: Signs of PH on echocardiography as defined here was found in 14% and had prognostic significance in COPD. A value of NT-proBNP less than 95 ng/l may be used to exclude signs of PH.

Background: Pulmonary hypertension (PH) is an important complication to interstitial lung disease (ILD). The aim of the present study was to investigate the prevalence and impact of PH on prognosis and exercise capacity in ILD patients., Methods: 212 ILD patients were screened for PH by echocardiography. Criteria for PH were either a tricuspid pressure regurgitation gradient >40 mmHg, a tricuspid annular plane systolic excursion <1.8 cm or right ventricular dilatation. If possible, PH was confirmed by right heart catheterisation. Pulmonary function tests and 6 min walk tests (6MWT) were performed., Results: 29 patients (14%) had PH, 16 (8%) had mild and 13 (6%) had severe PH (mean pulmonary artery pressure ≥ 35 mmHg). Compared to patients without PH, lung function parameters were lower in PH patients, a larger proportion had idiopathic pulmonary fibrosis (IPF) (41 vs 21%, p = 0.006), and the hazard ratio for death was 8.5 (95% CI: 4-17). After correction for lung function parameters and the presence of IPF, 6MWT was significantly lower in patients with PH compared to non-PH patients (difference ± SEM: 58 ± 22 m, p = 0.01)., Conclusions: PH occurred in 14% of a cohort of patients with ILD and was associated to IPF and lower lung function parameters. Mortality was markedly higher in PH patients, and the presence of PH reduced 6MWT independently of lung function and the presence of IPF. The present results emphasize the need for intensified treatment of patients with ILD and PH., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by pulmonary vasoconstriction, pulmonary arterial remodeling, abnormal angiogenesis and impaired right ventricular function. Despite progress in pharmacological therapy, there is still no cure for PAH. The peptide apelin and the G-protein coupled apelin receptor (APLNR) are expressed in several tissues throughout the organism. Apelin is localized in vascular endothelial cells while the APLNR is localized in both endothelial and smooth muscle cells in vessels and in the heart. Apelin is regulated by hypoxia inducible factor -1α and bone morphogenetic protein receptor-2. Patients with PAH have lower levels of plasma-apelin, and decreased apelin expression in pulmonary endothelial cells. Apelin has therefore been proposed as a potential biomarker for PAH. Furthermore, apelin plays a role in angiogenesis and regulates endothelial and smooth muscle cell apoptosis and proliferation complementary and opposite to vascular endothelial growth factor. In the systemic circulation, apelin modulates endothelial nitric oxide synthase (eNOS) expression, induces eNOS-dependent vasodilatation, counteracts angiotensin-II mediated vasoconstriction, and has positive inotropic and cardioprotective effects. Apelin attenuates vasoconstriction in isolated rat pulmonary arteries, and chronic treatment with apelin attenuates the development of pulmonary hypertension in animal models. The existing literature thus renders APLNR an interesting potential new therapeutic target for PH.

Background: The peptide apelin is localised in the vascular endothelium and highly expressed in pulmonary tissue. The aim of this study was to investigate whether apelin could be a potential lung-derived plasma marker for pulmonary hypertension, and study the effect of apelin in pulmonary arteries., Methods: Apelin protein levels were measured in the lung, right ventricle, and plasma from normoxic and chronic hypoxic rats with pulmonary hypertension. Isolated intrapulmonary arteries were mounted in microvascular myographs and the effect of apelin investigated. Finally, the distribution of apelin receptors in pulmonary tissue was visualised by immunohistochemistry., Results: Total pulmonary apelin content was not changed by hypoxia. Right ventricular apelin concentrations and content were lower than in the lung, but increased substantially in hypoxia in correlation with right ventricular pressure. Plasma apelin did not reflect pulmonary or right ventricular apelin levels. In pulmonary arteries from normoxic rats, apelin inhibited vasoconstriction to endothelin-1 and angiotensin-II. However, in arteries from hypoxic rats, apelin failed to inhibit contraction to angiotensin-II and endothelin-1. No difference in immunoreaction for apelin receptors was found in lung sections and arteries from normoxic versus chronic hypoxic rats., Conclusions: Apelin changes in the right ventricle seem more specific for pulmonary hypertension than do changes in pulmonary tissue, which does not speak in favour of apelin as a lung-derived marker for this disease. During normoxic conditions, apelin has a modulating effect on vasoconstriction which is lost in chronic hypoxia. This may reflect alterations in the signal transduction downstream of the apelin receptor.

The present study investigated whether activation of vasodilatory mechanisms masks the involvement of endothelin in hypoxic pulmonary vasoconstriction. Rat intrapulmonary arteries were mounted in microvascular myographs. In arteries with endothelium and contracted with phenylephrine, hypoxia, evoked by exchanging 5% CO2 in air for CO2 in N2, caused a transient contraction followed by a sustained contraction. Hypoxia evoked relaxation in preparations without endothelium. An inhibitor of ATP-sensitive K+ channels (KATP), glibenclamide (10 microM), blunted hypoxic relaxation in arteries without endothelium and enhanced the sustained hypoxic vasoconstriction in arteries with endothelium. Hypoxic contraction was more pronounced in endothelin compared with phenylephrine-contracted preparations in the absence, but not in the presence of glibenclamide. Antagonism of the endothelin ETA and ETB receptors with SB217242 or the combination of BQ123 and BQ788 inhibited endothelin and hypoxic contraction, but the latter only in the presence of glibenclamide. An inhibitor of nitric oxide (NO) synthase, N-nitro-L-arginine (100 microM), evoked contractions, which were left unaltered by SB217242 in hypoxic conditions. In conclusion, hypoxic contraction is mediated in part by an unknown endothelium-derived contractile factor and incubation with glibenclamide shows endothelin enhances hypoxic contraction in part through inhibition of KATP channels. Moreover, inhibition of NO formation in pulmonary arteries does not change endothelin receptor activation in severe hypoxia.

The present study addressed whether combined treatment with a phosphodiesterase type 5 inhibitor, sildenafil, and a nitric oxide donor, molsidomine, prevents development of pulmonary hypertension in chronic hypoxic rats. Two weeks of hypoxia increased right ventricular systolic pressure, and right ventricular and lung weight. Treatment with either sildenafil (10 mg/kg/day) or molsidomine (15 mg/kg/day) in drinking water reduced right ventricular systolic pressure and weight, while lung weight was unchanged. Combining sildenafil and molsidomine did not have additional effects compared to molsidomine alone. The number of muscularized pulmonary arteries with diameters below 50 microm was increased in vehicle and sildenafil-treated, but not in molsidomine-treated hypoxic rats. Acetylcholine relaxation was blunted in arteries from vehicle and molsidomine-treated, but not in sildenafil-treated rats. In conclusion, both sildenafil and molsidomine blunts pulmonary hypertension and right ventricular hypertrophy in chronic hypoxic rats, but no synergistic effects were observed.

Screening for diabetic retinopathy was introduced in Denmark in 1988. At present, screening is carried out in four of the 14 counties, thus being available to a minority of diabetic subjects. According to the WHO but also the National Board of Health, all diabetic patients should undergo screening for diabetic retinopathy. Not only does screening pay off in terms of preservation of vision, it is also cost-effective, as confirmed in the present study. The first fully digitized clinic for retinopathic screening in diabetic patients was recently introduced in the County of North Jutland. Preliminary results from this clinic indicate that all procedures can be handled in this fully digitized system. We therefore predict that fully digitized clinics for retinopathic screening will be introduced throughout Denmark in the future.