Benzodiazepines are a cornerstone in the treatment of alcohol withdrawal symptoms, although their use is associated with a risk of sedation leading to respiratory depression. This study describes the reasons for and frequency of Intensive Care Unit (ICU) admission, mechanical ventilation, and clinical outcomes for patients receiving symptom-triggered treatment with chlordiazepoxide for alcohol withdrawal symptoms. This retrospective quality-improvement study included admissions to a Danish general ICU after treatment with at least 200 mg chlordiazepoxide for alcohol withdrawal symptoms within 10 days before ICU admission. The primary outcome was the need for mechanical ventilation and secondary outcomes included 90-day hospital- and ICU readmission and mortality. The admissions were divided into two groups: "Too sedated" and "Too agitated" depending on the reason for ICU admission. A total of 113 patients with 133 admissions were included. The most common reasons for ICU admissions were respiratory insufficiency (39%) and somnolence (39%). Invasive or non-invasive mechanical ventilation was used in 71% of the ICU admissions (81% in the "Too sedated" and 53% in the "Too agitated" group, respectively). Thirty-six percent of admissions were followed by readmission to the hospital and 14% by readmission to the ICU within 90 days. Admissions were followed by a 21% risk of mortality at 90 days in the "Too sedated" group, whereas no patients died within 90 days in the "Too agitated" group. Typical presentation of ICU admission was respiratory insufficiency and somnolence after symptom-triggered treatment with chlordiazepoxide for alcohol withdrawal symptoms. Mechanical ventilation was used in more than two-thirds of the admitted patients, and the risk of readmission and fatal outcome was high.

Cisplatin and other ototoxic agents such as vancomycin, quinine, and carboplatin are widely used in medical treatments but pose a significant risk of ototoxicity. This literature review investigates the incidence, severity, and characteristics of drug induced ototoxicity of nine drugs listed in the Danish summary of product characteristics (SmPC's), where each was found to contain an unclear reference to ototoxic related side effect. The main objective was to identify patterns in ototoxic outcomes and assess the effectiveness of interventions aimed at reducing hearing damage. A systematic search identified nine clinical studies on ototoxic effects and four on preventive measures. Studies varied in design, ranging from retrospective reviews to randomized controlled trials, and included diverse patient populations, ages, and disease types. Data were extracted on dosage, type of ototoxicity, measurement methods, and statistical significance. Findings showed that cisplatin is consistently associated with dose dependent, often irreversible, bilateral hearing loss, with symptoms sometimes appearing weeks to months after treatment. Other agents like quinine and vancomycin presented more variable outcomes. Among preventive strategies, trans tympanic injections of N-acetylcysteine and sodium thiosulfate showed promising results in reducing cisplatin induced hearing loss, while oral antioxidants yielded limited effects. The review highlights methodological challenges, including heterogeneity in study design, limited follow up, and small sample sizes. There is also a possibility that additional relevant studies exist in other databases or under alternative search terms. Cisplatin presents the most well documented ototoxic profile, whereas the evidence for other drugs is either limited, variable, or lacking. These findings call for better harmonization between drug labelling and current clinical evidence, as well as improved monitoring and drug specific research to guide safer prescribing practices.

The Danish Poison Information Centre (DPIC) received 1827 enquiries from Greenland in the period 2007-2022. The risk and the treatment of poisonings in Greenland are potentially different from those in Denmark. The use and availability of medicines, the ethnicity and the vicinity of health care are different in Greenland compared with Denmark. This study examined whether the toxicological profile was different between Denmark and Greenland using DPIC data. The most frequent drug poisoning in Greenland was paracetamol, followed by ibuprofen and quetiapine (6.6, 4.5 and 1.6 enquiries/1000 inhabitants, respectively). There were significantly more serious poisonings in Greenland compared with Denmark (36% vs. 12% moderate or life-threatening poisonings; p = 0.0004). Most of the calls from Greenland to the DPIC came primarily from health care professionals (HCPs). Also, the age groups of the poisoned patients were different in Greenland compared with Denmark. In Denmark, 38% of the enquiries were regarding children aged 0-4, compared with 17% in Greenland. In the age group 20-29 years, 14% came from Denmark and 23% from Greenland. In conclusion, we found an excessive number of calls to the DPIC from HCPs in Greenland with more serious poisonings, primarily with paracetamol, and fewer calls regarding children.

Dental pain is common, and many patients use analgesics to alleviate the pain. Analgesics are readily accessible, and overdosing may lead to severe complications. This study explores the extent of analgesic overdosing in patients with dental pain. Data were collected from two dental emergency clinics in Copenhagen, Denmark, via questionnaires and interviews with 180 patients. Results showed that 82.8% (n = 149) had taken at least one type of analgesic, and 9% (n = 15) had exceeded the recommended maximum dosage. Of all patients with dental pain, 75.6% (n = 136) used paracetamol, 54.4% (n = 98) ibuprofen, 10% (n = 18) opioids, and 11.1% (n = 20) other types of analgesics. Most frequently, the pain was of pulpal origin (n = 119; 66.1%). Of all analgesics used, most were obtained places where guidance should be available, for example, pharmacies, dental clinics or hospitals (n = 152; 54%). The patients were aware of the recommended maximum daily dosage for paracetamol and ibuprofen in 39% (n = 70) and 41% (n = 73) of the cases, respectively. In conclusion, most patients with dental pain use analgesics to alleviate their pain. A substantial proportion of these patients overdose themselves, potentially putting them at risk of severe systemic complications. This study highlights the need for better patient education and safer pain management strategies.

Population pharmacokinetic models can potentially provide suggestions for an initial dose and the magnitude of dose adjustment during therapeutic drug monitoring procedures of imatinib. Several population pharmacokinetic models for imatinib have been developed over the last two decades. However, their predictive performance is still unknown when extrapolated to different populations, especially children. This study aimed to evaluate the predictive performance of these published models on an external real-world dataset containing data from both adults and children. A real-world dataset was collected, containing observations from adult and pediatric patients with Philadelphia chromosome-positive/Philadelphia chromosome-like acute lymphoblastic leukemia and chronic myeloid leukemia (N = 39) treated with imatinib. A systematic review through PubMed was conducted to identify qualified population-pharmacokinetic models for external evaluation (i.e., prediction-based, simulation-based, and Bayesian forecasting diagnostics). Standard allometric scaling was used for models that were developed based on data from adults only. Fifteen published models were found for evaluation, of which only two were based on data from both children and adults. Prediction-based diagnostics showed that some models had an acceptable level of bias. The model by Shriyan et al. (with allometric scaling) performed best with a median prediction error of 1.24

There is an unsettled concern that treatment with aromatase inhibitors (AIT) may adversely affect lipid-levels. In light of the improved survival of women with breast cancer and increased risk of atherosclerotic cardiovascular disease in older people, unfavorable effects on lipid-levels may represent a significant health concern for this group of patients. We used linked data from nationwide registries, including a clinical breast cancer database with information about allocated and dispensed AIT. Based on these, we investigated changes in plasma lipid-levels (primary outcome: low-density lipoprotein (LDL)-cholesterol, secondary outcomes: high-density lipoprotein (HDL)-cholesterol, total cholesterol, and triglycerides) following AIT in a nationwide cohort of postmenopausal women with early breast cancer, Denmark, 2009–2020. Included women had at least one LDL-cholesterol measurement before and after breast cancer diagnosis. Exposure was allocated and dispensed AIT as compared with not allocated to and no dispensed AIT. Outcome was the adjusted difference in lipid-level-change (from before to after breast cancer diagnosis) according to AIT. Among 10,461 women, there were 22,693 pre-breast cancer LDL-cholesterol measurements and 42,750 post-breast cancer LDL-cholesterol measurements. Overall, 7919 of the women were exposed to AIT and 2542 women were unexposed. For AIT exposed, the LDL-cholesterol-change was − 0.16 mmol/L (mM), and for unexposed, − 0.15 mM, respectively. The corresponding adjusted difference in LDL-cholesterol change for AIT exposed versus unexposed was − 0.03 mM (95% CI − 0.07 to 0.003). We found similar results in analysis of secondary outcomes. This study does not support the concern that AIT adversely affects lipid-levels.

INTRODUCTION:Therapeutic drug monitoring (TDM) is important to optimize drug exposure and minimize toxicity for the individual patient. AREAS COVERED:This narrative review covers the pharmacokinetics (PK), -dynamics (PD) and -genetics of classic chemotherapeutic drugs used in frontline therapy for acute lymphoblastic leukemia (ALL), including anthracyclines, asparaginase, busulfan, cyclophosphamide, cytarabine, glucocorticoids, methotrexate, nelarabine, thiopurines, tyrosine kinase inhibitors, and vincristine. Furthermore, novel immunotherapies including blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor T-cells that are rapidly moving into frontline therapy are addressed. This review focuses on TDM already used in clinical practice as well as the unused potential and feasibility of TDM. Finally, important factors affecting PK/PD such as obesity and transition to adolescence and young adulthood are discussed. EXPERT OPINION:Investigation of TDM as standard of care for antileukemic agents is highly warranted to personalize curative yet toxic anticancer regimens within frontline ALL treatment. Some of the drugs have been used in ALL treatment regimens for decades, but a wide range of new compounds are being introduced, some like blinatumomab reaching standard-of-care designation. Not least, optimized drug efficacy and reduction of the risk of serious toxicities may render TDM implementation cost-effective.

BACKGROUND: Use of anabolic androgenic steroids (AASs) is associated with increased mortality, and case reports have suggested that some of these deaths are due to cardiovascular disease. However, the epidemiology of cardiovascular disease in AAS users is still relatively unexplored. This study aimed to measure the incidence of cardiovascular disease in male AAS users and to compare these rates with those of a cohort from the general population matched by age and sex. METHODS: Men sanctioned in an antidoping program for AAS use in Danish fitness centers between 2006 and 2018 were included and matched for age and sex with 50 times as many controls from the general Danish population. The cohort was followed until June 30, 2023. Using the nationwide registries, we obtained information on admissions, prescriptions, educational length, and occupational status for both the AAS users and controls. This study investigated the incidence of acute myocardial infarction, percutaneous coronary intervention, or coronary artery bypass graft, venous thromboembolism, ischemic stroke, arrhythmia, cardiomyopathy, heart failure, and cardiac arrest during the follow-up period. RESULTS: During an average of 11 years of follow-up, AAS users (n=1189) demonstrated a significantly higher incidence of several cardiovascular events compared with controls (n=59 450). Correspondingly, AASs were associated with an increased risk of acute myocardial infarction (adjusted hazard ratio [aHR] 3.00 [95% CI, 1.67-5.39]), percutaneous coronary intervention or coronary artery bypass graft (aHR 2.95 [95% CI, 1.68-5.18]), venous thromboembolism (aHR 2.42 [95% CI, 1.54-3.80]), arrhythmias (aHR 2.26 [95% CI, 1.53-3.32]), cardiomyopathy (aHR 8.90 [95% CI, 4.99-15.88]), and heart failure (aHR 3.63 [95% CI, 2.01-6.55]). Due to the limited number of ischemic stroke and cardiac arrest cases among AAS users, these outcomes were not reportable. CONCLUSIONS: AAS use is associated with a substantially increased risk of cardiovascular disease in a large cohort with a long follow-up period.

INTRODUCTION:This study describes opioid and benzodiazepine poisonings in Denmark from 2014 to 2022. The analgesic effect of opioids and sedative effect of benzodiazepines are used to treat pain, insomnia and anxiety disorders and can cause abuse and addiction. MATERIALS AND METHODS:A retrospective observational register study with data from the Danish Poison Information Centre with alprazolam, clonazepam, oxazepam, buprenorphine, diacetylmorphine, methadone, morphine, oxycodone and tramadol poisonings. Multiple recordings of the same exposure are only registered once. RESULTS:Totally 10 965 enquiries were included with a 55/43% female/male ratio (2% unaccounted). The number of enquiries regarding poisonings with alprazolam increased from 56 in 2014 to 289 in 2022 (+416%) or from 2.27 to 7.71 per 1000 enquiries to the DPIC (+240%). The corresponding numbers regarding the other eight substances were buprenorphine [22/33 (+50%); 0.89/0.88 (-1%)], morphine [125/250 (+100%); 5.06/6.67 (+32%)], oxazepam [240/364 (+52%); 9.71/9.71 (0%)], oxycodone [44/199 (+352%); 1.78/5.31 (+198%)], tramadol [262/421 (+61%); 10.6/11.23 (+6%)], methadone [65/63 (-3%); 2.63/1.68 (-36%)], clonazepam [60/92 (+53%); 2.43/2.45 (+1%)] and diacetylmorphine [17/20 (+18%); 0.69/0.53 (-23%)]. CONCLUSION:In our 9-year study period, we observed large increases in poisonings with alprazolam and oxycodone. In the remaining drugs examined, we observed no change or even a reduction of the poisonings when adjusted for the general increase in enquiries to the DPIC.

Background: For aromatase inhibitor treatment (AIT) in breast cancer, there is an unresolved concern about ischaemic cardiotoxicity. We investigated the association between AIT and ischaemic cardiotoxicity in a prospective cohort of female patients with early breast cancer who received contemporary treatment in Denmark. Methods: In this prospective cohort study in Denmark, we identified postmenopausal patients of any age diagnosed with breast cancer as recorded in the nationwide Danish Breast Cancer Cooperative Group (DBCG) clinical database between Jan 1, 2009, and Dec 31, 2020, and linked them to other nationwide registries. Exclusion criteria included having a history of other primary cancer, less than 2 years of residency in Denmark, and no inclusion in a treatment protocol according to the DBCG database, including for metastatic or locally advanced breast cancer. Information on demography, hospital diagnoses, filled prescriptions, laboratory testing, and socioeconomic status were recorded. We stratified the patient cohort according to history (yes vs no) of selected cardiovascular disease defined as ischaemic heart disease, ischaemic stroke, and heart failure, and defined the primary outcome as two-point major adverse cardiovascular events (MACE; acute myocardial infarction or ischaemic stroke). We estimated cause-specific hazard ratios (HRs) according to allocation to AIT versus not in an intention-to-treat analysis using a Cox proportional hazards regression model with age as the underlying time scale, adjusting for demographic characteristics, tumour characteristics, and other anti-cancer treatments. Findings: 43 440 postmenopausal patients diagnosed with breast cancer were identified, of whom 32 635 were followed up and included in analyses. Of 29 118 postmenopausal patients with no history of selected cardiovascular disease, we observed 510 two-point MACEs among 22 135 patients allocated to AIT (incidence rate 43/1000 person-years of follow-up) and 170 two-point MACEs among 6983 patients not allocated to AIT (41/1000 person-years). The adjusted HR was 091 (95% CI 073-114) for patients allocated to AIT versus patients not allocated to AIT. Among 3517 patients with a history of selected cardiovascular disease, we observed 158 two-point MACEs among 2661 patients allocated to AIT (incidence rate 124/1000 person-years) and 50 two-point MACEs (121/1000 person-years) among 856 patients not allocated to AIT (adjusted HR 081 [95% CI 058-115]). Interpretation: Our findings do not support a clinically relevant ischaemic cardiotoxic potential of AIT in patients with early breast cancer and do not support avoiding AIT prescription in patients with early breast cancer.

N-acetylcysteine (NAC) is regarded as an effective treatment of paracetamol overdoses. However, in cases of "massive" paracetamol overdoses, recent studies indicate that patients may not be sufficiently treated with the standard dose of NAC (300 mg/kg over 20-21 h). The subject is further complicated because "massive overdoses" and "high-risk" are defined differently; some studies use the ingested amount (e.g., >40 g), and some studies use blood concentrations of paracetamol and transaminases. This narrative review investigates whether high-dose NAC significantly decreases the risk of hepatotoxicity in patients with massive paracetamol overdoses. Three observational studies were analysed; one study with 373 patients found no significant difference (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 0.49-3.29). One study with 79 patients found a significant difference (OR: 0.27, 95% CI: 0.08-0.94). The third study with 89 patients found a significant difference in hepatoxicity between the groups (p = 0.043). There are no solid evidence to support that treatment with high-dose NAC significantly reduces the rate of hepatotoxicity in patients presenting with massive paracetamol overdoses. Differences in inclusion criteria in the included studies make the studies incomparable. This paper shows that standardized inclusion is needed to determine whether a high-dose NAC regimen should be included in clinical practice.

BACKGROUND:Treatment with opioids is a mainstay in perioperative pain management. While the leading treatment paradigm has been procedure-specific pain management, efforts regarding personalized pain treatment are increasing. The OPI•AID project aims to develop personalized algorithms for perioperative pain management, taking demographic, surgical, and anaesthesiologic factors into account. We will undertake five parallel reviews to illuminate current evidence on different aspects of individual responses to perioperative opioid treatment. METHODS:Inclusion of adult populations in English-written studies. Review-specific searches are developed for the following databases: CENTRAL, MEDLINE, Embase, clinicaltrials.gov, and clinicaltrial.eu. Two authors will independently screen citations, extract data, and assess the risks of bias in each review (QUIPS, PROBAST and RoB2, as relevant). CONCLUSION:These reviews will evaluate various aspects of perioperative opioid treatment, including individualized treatment strategies, selection of specific opioids, and individual patient responses. These will guide future development of a personalized perioperative opioid treatment algorithm (OPI•AID) that will be validated and tested clinically against standard of care.