Discharge Information About Adverse Drug Reactions Indicates Lower Self-Reported Adverse Drug Reactions and Fewer Concerns in Patients After Percutaneous Coronary Intervention.

AIM: There are discrepancies between the information patients desire about adverse drug reactions (ADRs) and the information they receive from healthcare providers; this is an impediment to shared decision-making. This study aimed to establish whether patients received information about ADRs resulting from prescribed pharmacotherapy, before hospital discharge, after percutaneous coronary intervention (PCI) and to determine whether receiving information about ADRs was associated with incidence of self-reported ADRs or concerns related to prescribed pharmacotherapy. METHODS: CONCARDPCI, a prospective multicentre cohort study including 3,417 consecutive patients after PCI, was conducted at seven high-volume referral PCI centres in two Nordic countries. Clinical data were collected from patients' medical records and national quality registries. Patient-reported outcome measures were registered 2 months (T1), 6 months (T2), and 12 months (T3) after discharge. Covariate-adjusted logistic regression yielded adjusted odds ratios (aORs) with 95% confidence intervals (CIs). RESULTS: At discharge, 38% of participants had been informed about potential ADRs. For these patients, the incidence of self-reported ADRs was significantly lower at T1 (aOR 0.61, 95% CI 0.50-0.74; p<0.001), T2 (aOR 0.60, 95% CI 0.49-0.74; p<0.001), and T3 (aOR 0.57, 95% CI 0.46-0.71; p<0.001). Those who were not informed reported higher levels of concern about prescribed pharmacotherapy at all measuring points (p<0.001 for all comparisons). Those living alone (aOR 0.73, 95% CI 0.57-0.92; p=0.008), who were female (aOR 0.57, 95% CI 0.44-0.72; p<0.001), and with three or more versus no comorbidities (aOR 0.61, 95% CI 0.44-0.84; p=0.002) were less likely to receive information. CONCLUSION: A substantial proportion of patients were not informed about potential ADRs from prescribed pharmacotherapy after PCI. Patients informed about ADRs had lower incidences of self-reported ADRs and fewer concerns about prescribed pharmacotherapy.

A Patient With Sepsis-Induced Multiorgan Failure and Increasing Serum Methadone Concentration: A Case Study.

ABSTRACT: The authors describe a patient with substance use disorder admitted to the hospital with septic shock and multiorgan failure, in whom the serum concentration of methadone kept increasing despite discontinuation of the drug. Therapeutic drug monitoring was performed to monitor the methadone serum concentration during treatment of the underlying diseases.

Serum or Plasma for Quantification of Direct Oral Anticoagulants?

BACKGROUND: Direct oral anticoagulants are increasingly replacing vitamin K antagonists for prevention of stroke in patients with atrial fibrillation, partly owing to the lack of a need for routine monitoring. Therapeutic drug monitoring may still be warranted under certain circumstances. It is generally assumed that serum and plasma can be interchangeably used for this purpose. The aim of this study was to investigate possible differences between the serum, citrate-plasma, and ethylenediaminetetraacetic acid (EDTA)-plasma concentrations of apixaban and rivaroxaban in a larger patient group and their relation to factor X measurements. METHODS: Plasma and serum samples were drawn during the same venipuncture from patients treated with apixaban or rivaroxaban. Drug levels were measured using ultrahigh-performance liquid chromatography combined with tandem mass spectrometry. Three sample matrices were obtained from 8 healthy volunteers for measurement of factor X antigen and activity. RESULTS: Mean concentrations of apixaban and rivaroxaban were 16.8% and 36.6% higher in serum than in citrate-plasma, respectively (both P < 0.001). The corresponding differences in serum versus EDTA-plasma were 4.5% for apixaban and 13.1% for rivaroxaban (both P < 0.001). Factor X antigen measurements in citrate-plasma, EDTA-plasma, serum with clot activator, and serum without additives yielded comparable results, and factor X activity was significantly higher in serum than in plasma. CONCLUSIONS: Apixaban and rivaroxaban concentrations were significantly higher in serum than in plasma. The difference was more pronounced with rivaroxaban and was larger between serum and citrate-plasma than between serum and EDTA-plasma. Higher factor X activity in serum may explain the observed concentration differences. The choice of matrix is, thus, important when interpreting therapeutic drug monitoring results and in research involving analyses of direct oral anticoagulants. The authors recommend citrate-plasma as the preferred matrix.

Identifying target areas of medicines information efforts to pregnant and breastfeeding women by reviewing questions to SafeMotherMedicine: A Norwegian web-based public medicines information service.

BACKGROUND: Online information about safety of medications during pregnancy and breastfeeding is shown to be conflicting, resulting in anxiety and abstaining from use. The aim of this study was to characterize questions to SafeMotherMedicine, a web-based medicines information service for pregnant and breastfeeding women, to identify target areas that could guide subsequent development of medicines information directed at pregnant and breastfeeding women. METHODS: The SafeMotherMedicine database contains all questions received through the web-based service and their corresponding answers. A retrospective database analysis of questions received from January 2016 to September 2018 was performed, using descriptive statistics. RESULTS: A total of 11 618 questions were received including 5 985 questions (51.5%) concerning pregnancy, 4 878 questions (42.0%) concerning breastfeeding, and 755 questions (6.5%) concerning both conditions. The medications in question represented all therapeutic groups with paracetamol (7.0%), ibuprofen (4.1%), cetirizine (3.3%), desloratadine (3.2%) and meclizine (2.8%) being the top five. The 20 medications most frequently asked about for either pregnancy, breastfeeding or both pregnancy and breastfeeding, constituted half of all questions and were used to identify target areas. These included both symptomatic relief of common complaints, such as pain, nausea, and rhinitis, as well as treatment of chronic conditions such as allergy, psychiatric disorders, and asthma. Analysis of a subset of questions showed that most of these questions were asked before use of medications in a current pregnancy (49%) or during breastfeeding (72%). The questions concerned use of medications in all stages of pregnancy and breastfeeding. For 81.6% of the questions concerning pregnancy, and for 84.2% of the questions concerning breastfeeding, information of no or low risk for the foetus or the breastfed infant was provided by SafeMotherMedicine. CONCLUSIONS: We found that target areas for medicines information directed at pregnant and breastfeeding women included both symptomatic relief of common complaints as well as treatment of chronic conditions. The questions concerned a wide range of medications and involved use in all stages of pregnancy and breastfeeding. Our findings indicate that developing medicines information addressing the identified target areas will meet the information need for a large proportion of this patient group.

Intracellular Cytidine Deaminase Regulates Gemcitabine Metabolism in Pancreatic Cancer Cell Lines.

Cytidine deaminase (CDA) is a determinant of in vivo gemcitabine elimination kinetics and cellular toxicity. The impact of CDA activity in pancreatic ductal adenocarcinoma (PDAC) cell lines has not been elucidated. We hypothesized that CDA regulates gemcitabine flux through its inactivation and activation pathways in PDAC cell lines. Three PDAC cell lines (BxPC-3, MIA PaCa-2, and PANC-1) were incubated with 10 or 100 µM gemcitabine for 60 minutes or 24 hours, with or without tetrahydrouridine, a CDA inhibitor. Extracellular inactive gemcitabine metabolite (dFdU) and intracellular active metabolite (dFdCTP) were quantified with liquid chromatography tandem mass spectrometry. Cellular expression of CDA was assessed with real-time PCR and Western blot. Gemcitabine conversion to dFdU was extensive in BxPC-3 and low in MIA PaCa-2 and PANC-1, in accordance with their respective CDA expression levels. CDA inhibition was associated with low or undetectable dFdU in all three cell lines. After 24 hours gemcitabine incubation, dFdCTP was highest in MIA PaCa-2 and lowest in BxPC-3. CDA inhibition resulted in a profound dFdCTP increase in BxPC-3 but not in MIA PaCa-2 or PANC-1. dFdCTP concentrations were not higher after exposure to 100 versus 10 µM gemcitabine when CDA activities were low (MIA PaCa-2 and PANC-1) or inhibited (BxPC-3). The results suggest a regulatory role of CDA for gemcitabine activation in PDAC cells but within limits related to the capacity in the activation pathway in the cell lines. SIGNIFICANCE STATEMENT: The importance of cytidine deaminase (CDA) for cellular gemcitabine toxicity, linking a lower activity to higher toxicity, is well described. An underlying assumption is that CDA, by inactivating gemcitabine, limits the amount available for the intracellular activation pathway. Our study is the first to illustrate this regulatory role of CDA in pancreatic ductal adenocarcinoma cell lines by quantifying intracellular and extracellular gemcitabine metabolite concentrations.

SafeMotherMedicine: Aiming to Increase Women's Empowerment in Use of Medications During Pregnancy and Breastfeeding.

PURPOSE: Approximately 80% of pregnant women use medications. There is a need for evidence based medicines information that provide realistic risk estimates as pregnant and breastfeeding women tend to overestimate the risk of medications. The purpose of this paper is to describe the development and future perspectives of an innovative medicines information service aiming to increase empowerment among pregnant and breastfeeding women. DESCRIPTION: SafeMotherMedicine (SMM) (www.tryggmammamedisin.no) is a Norwegian medicines information service for pregnant and breastfeeding women. Established in 2011, the service was initially web-based only, in contrast to most teratology information services that at the time mainly operated using telephone and/or e-mail. ASSESSMENT: During the last eight years, SMM has provided close to 30,000 answers promoting appropriate medication use among pregnant and breastfeeding women. SMM launched a telephone-service in 2016, however, the annual number of questions received through the web-based service continues to increase. CONCLUSION: The service seems to have fulfilled a previously unmet need of evidence-based, individually tailored information about medications to pregnant and breastfeeding women in Norway. SMM empowers the women to make informed decisions regarding medication use in pregnancy and breastfeeding, thus contributing to person-centred medicine. The web-based design of the service may represent the pregnant and breastfeeding women's preferred way of communication.

Distribution of Psychotropic Drugs Into Lipoproteins.

AIM: The aim of this pilot study was to investigate whether psychotropic drugs frequently analyzed in a routine therapeutic drug monitoring laboratory bind to low-density lipoproteins/very-low-density lipoproteins (LDL/VLDL) in human serum. METHODS: Drug concentrations in 20 serum sample pools containing one psychotropic drug each, and in the LDL/VLDL fractions extracted from the same samples, were measured by triple quadrupole liquid chromatography tandem mass spectrometry. The membrane permeability of the drugs was measured using a Parallel Artificial Membrane Permeability Assay. RESULTS: Of the 20 antidepressants, antipsychotics, and antiepileptics examined, 7 drugs were detected in both the pooled serum samples and in the LDL/VLDL fraction. Binding of drugs to LDL/VLDL significantly correlated with high octanol: water partition coefficient (logP), high degree of protein binding, and a low polar surface area. The drugs found in LDL/VLDL, with the exception of aripiprazole, were also characterized by high or intermediate membrane permeability. CONCLUSIONS: The present results indicate that psychotropic drugs with certain characteristics bind to LDL/VLDL in blood. This further implies that lipoproteins could play an important role in drug transport.

Drug information centres and their provision of decision support: The Scandinavian experience.

WHAT IS KNOWN AND OBJECTIVE: Appraisal of drug information centres (DICs) is mainly by word of mouth communication and surveys of overall user satisfaction. Efforts to study the impact of this type of informatics and decision support systematically are generally lacking within the healthcare system. COMMENT: Scandinavian DICs question-answering databases are relevant sources for identifying recurring problems in pharmacotherapy, including drug safety questions, and for re-use of previous answers. Recent studies in this setting have shown that high-quality answers demand easily accessible literature sources, skills in literature search and critical assessment of the retrieved documentation. Furthermore, patient-specific advice in clinical cases presented within a requested time frame is appraised by clinicians. WHAT IS NEW AND CONCLUSIONS: Effective decision support by Scandinavian DICs depends on skills among staff and technological resources. Our experience could motivate further studies investigating methods and evaluating the impact of DICs in the healthcare system.

A retrospective comparison of inappropriate prescribing of psychotropics in three Norwegian nursing homes in 2000 and 2016 with prescribing quality indicators.

BACKGROUND: Inappropriate prescribing of psychotropics is a persistent and prevalent problem in nursing homes. The present study compared inappropriate prescribing of psychotropics in nursing homes 16 years apart with prescribing quality indicators. The purpose was to identify any change in inappropriate prescribing of relevance for medical informatics. METHODS: Three Norwegian nursing homes were audited in 2000 and 2016 with regard to prescribing quality. Psychotropics among 386 patients in 2000, and 416 patients in 2016, included combinations of antidepressants, antipsychotics, anxiolytics-hypnotics, and antiepileptics. Prescribing quality indicators included psychotropic polypharmacy (defined as concurrent use of three or more psychotropics) and potential inappropriate psychotropic substances or combinations. Furthermore, potential clinically relevant psychotropic interactions were classified as pharmacodynamic or pharmacokinetic using an interaction database. The first ranked (most important) interaction in each patient was selected with the following importance of categories in the database; recommended action > documentation > severity. Three levels (from low to high) within each category were used for ranking. RESULTS: From 2000 to 2016, psychotropic polypharmacy increased from 6.2 to 29.6%, potential inappropriate psychotropic substances was reduced from 17.9 to 11.3% and potential inappropriate psychotropic combinations increased from 7.8 to 27.9%. Changes in polypharmacy and combinations were predominantly associated with prescribing of anxiolytics-hypnotics. Sixty-three patients (16.3%) had psychotropic interactions in 2000 increasing to 146 patients (35.1%) in 2016. The increase in interactions was associated with prescribing of antidepressants. First ranked interactions, more than 60% of all interactions in both years, were increasingly pharmacodynamic, from 69.9 to 91.0%. Interactions in 2016 were associated with a lower level of recommended action and documentation, but not severity compared to 2000. The inappropriate prescribing of antipsychotics and antiepileptics was reduced in 2016 compared to 2000. CONCLUSIONS: Using prescribing quality indicators we observed the importance of antidepressants and anxiolytics-hypnotics for inappropriate prescribing in 2016 while the role of antipsychotics and antiepileptics were reduced compared to 2000. A change to mainly pharmacodynamic interactions that lack good documentation was also observed. The present findings can be used for medical informatics-based approaches to address specific problems with prescribing, and prescribing quality indicators, in Norwegian nursing homes.

Physicians' questions concerning drug use among older patients: experience from Norwegian drug information centres (RELIS) in the period 2010-2015.

Questions from physicians to regional medicines information and pharmacovigilance centres in Norway (RELIS) concerning older patients were described. Question-answer pairs (QAPs) from the RELIS database indexed with the category "older", and concerning individual patients from the period 01 Jan 2010 to 31 Dec 2015, were analysed. Two-hundred and eight QAPs categorized with "older" were retrieved from a total of 16 710 in the study period, and 122 of 208 QAPs fulfilled the inclusion criteria. The most common categories of drugs in question (n = 228) according to the ATC system were N: Nervous system (30.3%) and C: Cardiovascular system (23.7%). Questions from physicians (n = 122) were most frequently about adverse effects (41.8%) and treatment (39.3%). The majority of questions to RELIS concerning older patients came from general practice (GP). The results suggest drug information efforts to GPs in care of older patients with regard to psychopharmacology and cardiovascular pharmacology.

Risk perception regarding drug use in pregnancy.

Pregnant women, but also physicians, have unrealistically high perceptions of teratogenic drug effects. This may result in suboptimal treatment of disease and even influence decisions of whether to continue pregnancy. To attain more realistic teratogenic risk perceptions, several factors that influence this issue should be considered, and these are further discussed in this Clinical Opinion. Importantly, drug use may have several benefits, both for the pregnant woman's health and to avoid negative fetal effects of untreated maternal disease. A greater focus on this aspect may act to balance risk perceptions. Furthermore, both pregnant women and physicians need access to drug information sources that provide realistic risk estimates to increase confidence in appropriate drug use and prescribing. We suggest that access to decision support and individually tailored information provided by drug information centers may contribute to this goal.

Quality assessment of structure and language elements of written responses given by seven Scandinavian drug information centres.

PURPOSE: The aim of this study was to identify structure and language elements affecting the quality of responses from Scandinavian drug information centres (DICs). METHODS: Six different fictitious drug-related queries were sent to each of seven Scandinavian DICs. The centres were blinded for which queries were part of the study. The responses were assessed qualitatively by six clinical pharmacologists (internal experts) and six general practitioners (GPs, external experts). In addition, linguistic aspects of the responses were evaluated by a plain language expert. RESULTS: The quality of responses was generally judged as satisfactory to good. Presenting specific advice and conclusions were considered to improve the quality of the responses. However, small nuances in language formulations could affect the individual judgments of the experts, e.g. on whether or not advice was given. Some experts preferred the use of primary sources to the use of secondary and tertiary sources. Both internal and external experts criticised the use of abbreviations, professional terminology and study findings that was left unexplained. The plain language expert emphasised the importance of defining and explaining pharmacological terms to ensure that enquirers understand the response as intended. In addition, more use of active voice and less compressed text structure would be desirable. CONCLUSIONS: This evaluation of responses to DIC queries may give some indications on how to improve written responses on drug-related queries with respect to language and text structure. Giving specific advice and precise conclusions and avoiding too compressed language and non-standard abbreviations may aid to reach this goal.

Factors associated with time consumption when answering drug-related queries to Scandinavian drug information centres: a multi-centre study.

PURPOSE: There is little research-based documentation on the services provided by drug information centres (DICs). The aim of this multi-centre study was to explore for the first time the factors associated with time consumption when answering drug-related queries at eight different but comparable DICs. METHODS: During an 8-week period, staff members at eight Scandinavian DICs recorded the number of minutes during which they responded to queries. Mixed model linear regression analyses were used to explore the factors associated with time consumption when answering queries. RESULTS: The mean time consumption per query was 178 min (range 4-2540 min). The mean time consumed per query increased by 28 (95 % confidence interval (CI) 23 to 33, p < 0.001) min higher for queries for which there was a lack of documentation and 139 (95 % CI 74 to 203, p < 0.001) min higher when conflicting information was present in the literature. Staff members with less than 1 year of experience consumed a mean of 91 more minutes (95 % CI 32 to 150, p = 0.003) per query than staff members with more than 2 years of experience. CONCLUSIONS: This study demonstrates the large variation in time consumed answering queries posed to Scandinavian DICs. The results highlight the need for highly competent staff members and easy access to drug information sources. Further studies are required to explore the association between time consumption and response quality.

Questions about complementary and alternative medicine to the Regional Medicines Information and Pharmacovigilance Centres in Norway (RELIS): a descriptive pilot study.

BACKGROUND: Provision of clinically relevant information about complementary and alternative medicine (CAM) to health care professionals is not well described. The aim of the study was to assess questions about CAM to the Regional Medicines Information and Pharmacovigilance Centres in Norway (RELIS). METHODS: All question-answers pairs (QAPs) in the RELIS database indexed with alternative medicine from 2005-2010 constituted the study material. A randomly selected sample of 100 QAPs was characterized with regard to type of question (category, patient-specific or general), occupation and workplace of enquirer, the type of information search performed (simple or advanced), and if the answers contained information to provide factual or consultative replies (facts about or advice on clinical use of CAM, respectively). Proportions were compared with Fisher's exact test with significance at the 0.05 level. RESULTS: One thousand and thirty-eight (7.7%) out of 13 482 questions involved CAM. Eighty-two out of 100 questions concerned products containing one or more herbs, vitamins and minerals as well as other substances. Thirty-eight out of 100 questions concerned the category documentation (substance identification and/or literature reports about clinical effects), 36 interactions, 16 adverse effects, 9 pregnancy and lactation, and 1 question concerned contraindications. Sixty-three questions were patient-specific and 37 general. Fifty-four questions came from physicians, 33 from pharmacists and 13 from others (including nurses, midwives, students, CAM practitioners, and the public). Pharmacists asked more frequently about interactions while physicians asked more frequently about adverse effects (p < 0.05). Seventy-six of the questions came from outside hospital, mainly general practice and community pharmacies. Fifty-nine answers were based on a simple and 41 on an advanced information search. Thirty-three factual and 38 consultative answers were provided. In 29 answers, search provided no information. Lack of information to provide an answer was not significantly different between patient-specific (31.7%) and general questions (24.3%). CONCLUSIONS: General practice and community pharmacies are the main sources for questions about CAM to RELIS. Physicians are concerned about adverse effects while pharmacists are concerned about interactions. Lack of information to provide answers to patient-specific and general questions about CAM represents a problem.