Extracellular Vesicles as Surrogates for the Regulation of the Drug Transporters ABCC2 (MRP2) and ABCG2 (BCRP).

Drug efflux transporters of the ATP-binding-cassette superfamily play a major role in the availability and concentration of drugs at their site of action. ABCC2 (MRP2) and ABCG2 (BCRP) are among the most important drug transporters that determine the pharmacokinetics of many drugs and whose overexpression is associated with cancer chemoresistance. ABCC2 and ABCG2 expression is frequently altered during treatment, thus influencing efficacy and toxicity. Currently, there are no routine approaches available to closely monitor transporter expression. Here, we developed and validated a UPLC-MS/MS method to quantify ABCC2 and ABCG2 in extracellular vesicles (EVs) from cell culture and plasma. In this way, an association between ABCC2 protein levels and transporter activity in HepG2 cells treated with rifampicin and hypericin and their derived EVs was observed. Although ABCG2 was detected in MCF7 cell-derived EVs, the transporter levels in the vesicles did not reflect the expression in the cells. An analysis of plasma EVs from healthy volunteers confirmed, for the first time at the protein level, the presence of both transporters in more than half of the samples. Our findings support the potential of analyzing ABC transporters, and especially ABCC2, in EVs to estimate the transporter expression in HepG2 cells.

Development and Pilot Testing of an Algorithm-Based Approach to Anticholinergic Deprescribing in Older Patients.

BACKGROUND: Adverse anticholinergic drug reactions are common, yet evidence on how to reduce exposure to anticholinergic activity and reliably measure successful deprescribing is still scant. This study proposes an algorithm-based approach to evaluate and reduce anticholinergic load, and reports the results of its pilot testing. METHODS: Based on published evidence and expert opinion, a list of 85 anticholinergic drugs and 21 algorithms for reducing anticholinergic load, e.g., by recommending alternative drugs with lower risk, were developed. An accompanying test battery was assembled by focusing on instruments that sensitively reflect anticholinergic load and may be sensitive to depict changes (Neuropsychological Assessment Battery to measure memory and attention, validated assessments for constipation, urinary symptoms, and xerostomia, as well as blood biomarkers). The approach was pilot-tested in a geriatric rehabilitation unit, with clinician feedback as the primary outcome and characterization of anticholinergic symptoms as the secondary outcome. The intervention was delivered by a pharmacist and a clinical pharmacologist who used the algorithms to generate personalized recommendation letters. RESULTS: We included a total of 20 patients, 13 with anticholinergic drugs and 7 without. Recommendations were made for 22 drugs in nine patients from the intervention group, of which seven letters (78%) were considered helpful and 8/22 (36%) anticholinergic drugs were discontinued, reducing anticholinergic load in seven patients. In contrast to patients without drug change, memory assessment in patients with reduced anticholinergic load improved significantly after 2 weeks (6 ± 3 vs. -1 ± 6 points). CONCLUSIONS: The approach was well received by the participating physicians and might support standardized anticholinergic deprescribing.

In vitro evaluation of the reductive carbonyl idarubicin metabolism to evaluate inhibitors of the formation of cardiotoxic idarubicinol via carbonyl and aldo-keto reductases.

The most important dose-limiting factor of the anthracycline idarubicin is the high risk of cardiotoxicity, in which the secondary alcohol metabolite idarubicinol plays an important role. It is not yet clear which enzymes are most important for the formation of idarubicinol and which inhibitors might be suitable to suppress this metabolic step and thus would be promising concomitant drugs to reduce idarubicin-associated cardiotoxicity. We, therefore, established and validated a mass spectrometry method for intracellular quantification of idarubicin and idarubicinol and investigated idarubicinol formation in different cell lines and its inhibition by known inhibitors of the aldo-keto reductases AKR1A1, AKR1B1, and AKR1C3 and the carbonyl reductases CBR1/3. The enzyme expression pattern differed among the cell lines with dominant expression of CBR1/3 in HEK293 and MCF-7 and very high expression of AKR1C3 in HepG2 cells. In HEK293 and MCF-7 cells, menadione was the most potent inhibitor (IC50 = 1.6 and 9.8 µM), while in HepG2 cells, ranirestat was most potent (IC50 = 0.4 µM), suggesting that ranirestat is not a selective AKR1B1 inhibitor, but also an AKR1C3 inhibitor. Over-expression of AKR1C3 verified the importance of AKR1C3 for idarubicinol formation and showed that ranirestat is also a potent inhibitor of this enzyme. Taken together, our study underlines the importance of AKR1C3 and CBR1 for the reduction of idarubicin and identifies potent inhibitors of metabolic formation of the cardiotoxic idarubicinol, which should now be tested in vivo to evaluate whether such combinations can increase the cardiac safety of idarubicin therapies while preserving its efficacy.

A Physiologically Based Pharmacokinetic Model of Ketoconazole and Its Metabolites as Drug-Drug Interaction Perpetrators.

The antifungal ketoconazole, which is mainly used for dermal infections and treatment of Cushing's syndrome, is prone to drug-food interactions (DFIs) and is well known for its strong drug-drug interaction (DDI) potential. Some of ketoconazole's potent inhibitory activity can be attributed to its metabolites that predominantly accumulate in the liver. This work aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model of ketoconazole and its metabolites for fasted and fed states and to investigate the impact of ketoconazole's metabolites on its DDI potential. The parent-metabolites model was developed with PK-Sim® and MoBi® using 53 plasma concentration-time profiles. With 7 out of 7 (7/7) DFI AUClast and DFI Cmax ratios within two-fold of observed ratios, the developed model demonstrated good predictive performance under fasted and fed conditions. DDI scenarios that included either the parent alone or with its metabolites were simulated and evaluated for the victim drugs alfentanil, alprazolam, midazolam, triazolam, and digoxin. DDI scenarios that included all metabolites as reversible inhibitors of CYP3A4 and P-gp performed best: 26/27 of DDI AUClast and 21/21 DDI Cmax ratios were within two-fold of observed ratios, while DDI models that simulated only ketoconazole as the perpetrator underperformed: 12/27 DDI AUClast and 18/21 DDI Cmax ratios were within the success limits.

Prescribing Cascades: How to Detect Them, Prevent Them, and Use Them Appropriately.

BACKGROUND: A prescribing cascade is the treatment of an adverse drug reaction (ADR) with another drug. In this review, we discuss (a) the different types of prescribing cascade and (b) the measures that can be taken so that they will be recognized and dealt with appropriately, both in the hospital and in the outpatient setting. METHODS: This review is based on pertinent publications retrieved by a selective literature search. RESULTS: The literature distinguishes intentional from unintentional prescribing cascades, and appropriate from inappropriate ones. We further distinguish prophylactic from therapeutic prescribing cascades and draw a line between those that are necessary and those that are merely appropriate. The following main questions are essential for dealing with prescribing cascades appropriately: (1) Did the precipitating drug cause a clinically relevant ADR or risk of an ADR? (2) Is the precipitating drug still indicated? (3) Can an ADR be avoided by altering the treatment with the precipitating drug, or by (4) switching to another drug instead? (5) Can the drug used to treat the ADR actually affect it beneficially? (6) Do the benefits of the prescribing cascade outweigh its risks? CONCLUSION: Prescribing cascades are not problematic in themselves; on the contrary, they are sometimes a necessary part of good prescribing practice. There is still a lack of practically implementable instruments to help physicians detect prescribing cascades reliably, assess them properly, and put them to appropriate use.

Evaluation of PepT1 (SLC15A1) Substrate Characteristics of Therapeutic Cyclic Peptides.

The human peptide transporter hPepT1 (SLC15A1), physiologically transporting dipeptides and tripeptides generated during food digestion, also plays a role in the uptake of small bioactive peptides and peptide-like drugs. Moreover, it might be addressed in prodrug strategies of poorly absorbed drugs. We hypothesised that the cyclic drug peptides octreotide and pasireotide could be substrates of this transporter because their diameter can resemble the size of dipeptides or tripeptides due to their strong structural curvature and because they reach the systemic circulation in Beagle dogs. For investigating possible hPepT1 substrate characteristics, we generated and characterised a CHO-K1 cell line overexpressing SLC15A1 by transfection and selection via magnetic beads. Possible inhibition of the uptake of the prototypical substrate Gly-Sar by octreotide and pasireotide was screened, followed by quantifying the uptake of the cyclic peptides in cells overexpressing SLC15A1 compared with the parental cell line. Although inhibition of Gly-Sar uptake was observed, uptake of octreotide and pasireotide was not increased in SLC15A1 overexpressing cells, indicating a lack of transport by hPepT1. Our data clearly indicate that octreotide and pasireotide are nonsubstrate inhibitors of hPepT1 and that their oral bioavailability cannot be explained by absorption via hPepT1.

Evaluation of CYP2C19 activity using microdosed oral omeprazole in humans.

PURPOSE: To investigate the suitability of microdosed oral omeprazole for predicting CYP2C19 activity in vivo in combination with simultaneous assessment of CYP3A and CYP2D6 activity using both microdosed midazolam and yohimbine. METHODS: An open, fixed-sequence study was carried out in 20 healthy participants. Single microdosed (100 µg) and therapeutic (20 mg) doses of omeprazole were evaluated without comedication and after administration of established CYP2C19 perpetrators fluconazole (inhibition) and rifampicin (induction). To prevent degradation of the uncoated omeprazole microdose, sodium bicarbonate buffer was administered. The pharmacokinetics of omeprazole and its 5-hydroxy-metabolite were assessed as well as the pharmacokinetics of midazolam and yohimbine to estimate CYP3A4 and CYP2D6 activity. RESULTS: Calculated pharmacokinetic parameters after administration of 100 µg and 20 mg omeprazole in healthy subjects suggest dose proportionality. Omeprazole clearance was significantly decreased by fluconazole from 388 [95% CI: 266-565] to 47.2 [42.8-52.0] mL/min after 20 mg omeprazole and even further after 100 µg omeprazole (29.4 [24.5-35.1] mL/min). Rifampicin increased CYP2C19-mediated omeprazole metabolism. The omeprazole hydroxylation index was significantly related to omeprazole clearance for both doses. Both fluconazole and rifampicin altered CYP3A4 activity whereas no change of CYP2D6 activity was observed at all. CONCLUSIONS: Microdosed oral omeprazole is suitable to determine CYP2C19 activity, also during enzyme inhibition and induction. However, the administration of sodium bicarbonate buffer also had a small influence on all victim drugs used. TRIAL REGISTRATION: EudraCT: 2017-004270-34.

Does the circulating ketoconazole metabolite N-deacetyl ketoconazole contribute to the drug-drug interaction potential of the parent compound?

Ketoconazole is a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and of P-glycoprotein (P-gp) and is often used as an index inhibitor especially for CYP3A4-mediated drug metabolism. A preliminary physiologically based pharmacokinetic (PBPK) model for drug-drug interactions indicated possible involvement of a metabolite to the perpetrator potential of ketoconazole. Still unknown for humans, in rodents, N-deacetyl ketoconazole (DAK) has been identified as the major ketoconazole metabolite. We therefore investigated in vitro, whether DAK also inhibits the human CYPs and drug transporters targeted by ketoconazole and quantified DAK in human plasma from healthy volunteers after receiving a single oral dose of 400 mg ketoconazole. Our data demonstrated that DAK also inhibits CYP3A4 (2.4-fold less potent than ketoconazole), CYP2D6 (13-fold more potent than ketoconazole), CYP2C19 (equally potent), P-gp (3.4-fold less potent than ketoconazole), breast cancer resistance protein (more potent than ketoconazole) and organic anion transporting polypeptide 1B1 and 1B3 (7.8-fold and 2.6-fold less potent than ketoconazole). After a single oral dose of 400 mg ketoconazole, maximum concentrations of DAK in human plasma were only 3.1 ‰ of the parent compound. However, assuming that DAK also highly accumulates in the human liver as demonstrated for rodents, inhibition of the proteins investigated could also be conceivable in vivo. In conclusion, DAK inhibits several CYPs and drug transporters, which might contribute to the perpetrator potential of ketoconazole.

Perpetrator Characteristics of Azole Antifungal Drugs on Three Oral Factor Xa Inhibitors Administered as a Microdosed Cocktail.

BACKGROUND: Factor Xa inhibitors (FXaIs) are increasingly used without having sufficient drug-drug interaction data. Using a microdosed cocktail methodology could support filling the knowledge gap quickly. METHODS: In a randomised crossover trial, we investigated the drug-drug interactions between six oral azole antifungals and a microdosed FXaI cocktail containing 25 µg rivaroxaban, 25 µg apixaban, and 50 µg edoxaban. Additionally, different enzyme activities were also monitored using a microdosed cocktail approach. The six different azole antifungals were administered in therapeutic doses over a 24 h period, while the microdosed cocktails were administered 1 h after administration of the azole antifungals. RESULTS: Ketoconazole and posaconazole were the strongest perpetrators, showing similar increases as apixaban (area under the concentration-time curve ratio [AUCR] 1.64 and 1.62, respectively) and edoxaban (AUCR 2.08 and 2.1, respectively), whereas ketoconazole increased rivaroxaban 2.32-fold but only increased posaconazole 1.37-fold. All other azole antifungals showed less perpetrator effects on the FXaIs. Cytochrome P450 (CYP) 3A inhibition was confirmed using microdosed midazolam, with ketoconazole also the most potent perpetrator (8.42-fold). CONCLUSION: Drug-drug interactions for three victim drugs of the same drug class (FXaIs) with different clearance mechanisms can be studied using a microdosed cocktail approach. Using members of the azole antifungal drug class as perpetrators, multiple interactions can be studied in one trial, and a more detailed insight into the underlying interaction mechanisms is possible. CLINICAL TRIAL REGISTRATION: EudraCT number: 2017-004453-16.

Changing the medication documentation process for discharge: impact on clinical routine and documentation quality-a process analysis.

OBJECTIVES: In 2017, an in-house best-practice process for medication documentation was developed and implemented to meet the new German legal requirements concerning the management of patient discharge from the hospital. Because this law regulates the common steps of good discharge practices (eg, specification of discharge mediation documentation), we used its implementation to assess the impact of such a measure on the quality of medication documentation and related workflows in clinical routine. METHODS: By observing workflows and interviewing the affected employees, we analysed the medication workflow processes from admission to discharge of seven representative departments of a large university hospital before and early after implementation of a newly defined best-practice process. To investigate the implementation impact, following measures were determined overall and for five key process steps: quality of medication documentation as measured by predefined criteria, the adherence to the best-practice process (range 0%-100%), workload and potential shifts in responsibilities. RESULTS: Already early after implementation, all departments met the legal requirements and the quality of the medication documentation increased from low to high quality in most departments. Mean adherence to the best-practice process was 77% (range 60%-100%) with strictest adherence of 100% in one department. Thereby, the number of process steps and hence, likely also the workload increased in all departments. New tasks were mainly performed by physicians and in one department by pharmacists. CONCLUSIONS: The new lawful best-practice process led to a higher quality in medication documentation at the cost of a higher workload for physicians, potentially limiting time for other care tasks. Therefore, it could be important to define areas of the medication documentation process in which physicians could be supported by other professions or new tools facilitating accurate medication documentation as the basis of continuity of care.

Factors That Influence Adherence to Medication in Adults With Congenital Heart Disease (ACHD).

Objective: Innovative operative and interventional procedures have improved survival in congenital heart disease (CHD), and today more than 90% of these children reach adulthood. Consequently, adherence and psychosocial issues are becoming increasingly important because non-adherence to treatment recommendations worsens morbidity and mortality. This study aimed to identify factors modifying adherence to medication in adult congenital heart disease (ACHD). Methods: This cross-sectional study included 451 outpatients (female 47.9%, average age ± SD: 37.9 ± 12 years) from the ACHD department, who completed a questionnaire assessing medication non-adherence and individual barriers to treatment. Further assessments included psychological well-being (Hospital Anxiety and Depression scale; HADS), childhood traumatization, sociodemographic, and clinical data. Binary logistic regression analysis calculated the impact of these factors on drug adherence. Results: Of the 451 patients 162 participants (35.9%) reported to be non-adherent. In univariate analysis non-adherence to treatment was associated with smoking (P = < 0.001) and internet addiction (P = 0.005). Further factors negatively influencing adherence were the presence of depressive symptoms (P = 0.002), anxiety (P = 0.004), and childhood traumatization (p = 0.002). Factors positively associated with adherence were older age (P = 0.003) and more advanced heart disease as indicated by NYHA class (P = 0.01), elevated NT-proBNP (P = 0.02), device therapy (P = 0.002) and intermittent arrhythmias (P = 0.01). In multivariate analysis especially psychopathological factors such as depression (P = 0.009), anxiety (P = 0.032) and childhood traumatization (P = 0.006) predicted non-adherence. Conclusion: Adherence is a critical issue in the long-term management of ACHD. Identifying modifiable factors that worsen adherence offers the opportunity for targeted interventions. Depressive symptoms, anxiety, and adverse childhood experiences are amenable to psychosocial interventions, as well as cigarette smoking. Our study suggests that a multimodal and interdisciplinary treatment concept for the long-term management of adults with congenital heart disease could be beneficial. Whether it will further improve morbidity and mortality, should be assessed in prospective interventions.

Estimated Thresholds of Minimum Necessary Adherence for Effective Treatment with Direct Oral Anticoagulants - A Retrospective Cohort Study in Health Insurance Claims Data.

BACKGROUND: An essential contribution regarding the prevention of thromboembolic events in patients with (non-valvular) atrial fibrillation (AF) is good adherence to direct oral anticoagulants (DOACs). However, it is an open question what "good" adherence means for DOACs or below which threshold non-adherence is clinically relevant for AF patients. Ultimately, such a classification could prevent strokes and associated costs through adjusted treatment regimens or supportive measures. METHODS: We selected 10,092 AF patients from health insurance claims data between 2014 and 2018 who were issued a majority (at least half of the number) of maximum approved strength prescriptions of one of the following DOACs, namely rivaroxaban, apixaban, or dabigatran. Due to the limited sample size, the prescriptions of dabigatran had to be finally excluded for the cut-off analysis. DOAC adherence was calculated as the proportion of days covered (PDC) by dividing the days of theoretical use (days covered) of the drug by the duration in days of the observation interval. PDC cut-off values were derived from stroke risk as a function of continuous PDC values in time-to-event analyses and corresponding dose-response models. The influence of adherence-promoting interventions (targeted and untargeted) on the occurrence of strokes and related costs was then projected, considering intervention costs per patient. RESULTS: The population had a mean age of 74.5 years and 50% were female. The median PDC was 0.79 ± 0.28 with a median follow-up time of 1218 days, in which 2% of all DOAC patients had a stroke. The adherence cut-offs for good adherence were identified at 0.78 for rivaroxaban and 0.8 for apixaban. Targeted interventions appeared to be far more cost-effective than untargeted interventions. CONCLUSION: Clear adherence cut-offs enable healthcare professionals to identify patients with clinically relevant non-adherence. Interventions based on these cut-offs appear to be a promising means to optimize DOAC treatment.

Predicting hospital admissions from individual patient data (IPD): an applied example to explore key elements driving external validity.

OBJECTIVE: To explore factors that potentially impact external validation performance while developing and validating a prognostic model for hospital admissions (HAs) in complex older general practice patients. STUDY DESIGN AND SETTING: Using individual participant data from four cluster-randomised trials conducted in the Netherlands and Germany, we used logistic regression to develop a prognostic model to predict all-cause HAs within a 6-month follow-up period. A stratified intercept was used to account for heterogeneity in baseline risk between the studies. The model was validated both internally and by using internal-external cross-validation (IECV). RESULTS: Prior HAs, physical components of the health-related quality of life comorbidity index, and medication-related variables were used in the final model. While achieving moderate discriminatory performance, internal bootstrap validation revealed a pronounced risk of overfitting. The results of the IECV, in which calibration was highly variable even after accounting for between-study heterogeneity, agreed with this finding. Heterogeneity was equally reflected in differing baseline risk, predictor effects and absolute risk predictions. CONCLUSIONS: Predictor effect heterogeneity and differing baseline risk can explain the limited external performance of HA prediction models. With such drivers known, model adjustments in external validation settings (eg, intercept recalibration, complete updating) can be applied more purposefully. TRIAL REGISTRATION NUMBER: PROSPERO id: CRD42018088129.

Time-Resolved Effect of Interferon-Alpha 2a on Activities of Nuclear Factor Kappa B, Pregnane X Receptor and on Drug Disposition Genes.

Interferon-alpha (IFN-α) is suggested to cause pharmacokinetic drug interactions by lowering expression of drug disposition genes through affecting the activities of nuclear factor kappa B (NF-ĸB) and pregnane X receptor (PXR). The time-resolved impact of IFN-α 2a (1000 U/mL; 5000 U/mL; 2 h to 30 h) on the activities of NF-ĸB and PXR and mRNA expression (5000 U/mL; 24 h, 48 h) of selected drug disposition genes and on cytochrome P450 (CYP3A4) activity in LS180 cells (5000 U/mL; 24 h, 48 h) was evaluated using luciferase-based reporter gene assays, reverse transcription polymerase chain reaction, and luminescence-based CYP3A4 activity assays. The cross-talk between NF-ĸB activation and PXR suppression was evaluated by NF-ĸB blockage (10 µM parthenolide). IFN-α 2a initially (2 h, 6 h) enhanced NF-ĸB activity 2-fold and suppressed PXR activity by 30%. mRNA of CYP3A4 was halved, whereas UGT1A1 was increased (1.35-fold) after 24 h. After 48 h, ABCB1 expression was increased (1.76-fold). CYP3A4 activity remained unchanged after 24 h, but was enhanced after 48 h (1.35-fold). IFN-α 2a demonstrated short-term suppressive effects on PXR activity and CYP3A4 mRNA expression, likely mediated by activated NF-ĸB. Longer exposure enhanced CYP3A4 activity. Clinical trials should evaluate the relevance by investigating the temporal effects of IFN-α on CYP3A4 using a sensitive marker substrate.

Low risk of the TMPRSS2 inhibitor camostat mesylate and its metabolite GBPA to act as perpetrators of drug-drug interactions.

Camostat mesylate, a potent inhibitor of the human transmembrane protease, serine 2 (TMPRSS2), is currently under investigation for its effectiveness in COVID-19 patients. For its safe application, the risks of camostat mesylate to induce pharmacokinetic drug-drug interactions with co-administered drugs should be known. We therefore tested in vitro the potential inhibition of important efflux (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2)), and uptake transporters (organic anion transporting polypeptides OATP1B1, OATP1B3, OATP2B1) by camostat mesylate and its active metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA). Transporter inhibition was evaluated using fluorescent probe substrates in transporter over-expressing cell lines and compared to the respective parental cell lines. Moreover, possible mRNA induction of pharmacokinetically relevant genes regulated by the nuclear pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) was analysed in LS180 cells by quantitative real-time PCR. The results of our study for the first time demonstrated that camostat mesylate and GBPA do not relevantly inhibit P-gp, BCRP, OATP1B1 or OATP1B3. Only OATP2B1 was profoundly inhibited by GBPA with an IC50 of 11 µM. Induction experiments in LS180 cells excluded induction of PXR-regulated genes such as cytochrome P450 3A4 (CYP3A4) and ABCB1 and AhR-regulated genes such as CYP1A1 and CYP1A2 by camostat mesylate and GBPA. Together with the summary of product characteristics of camostat mesylate indicating no inhibition of CYP1A2, 2C9, 2C19, 2D6, and 3A4 in vitro, our data suggest a low potential of camostat mesylate to act as a perpetrator in pharmacokinetic drug-drug interactions. Only inhibition of OATP2B1 by GBPA warrants further investigation.

Short and mid-term impact of community pharmacy-based medication reviews on medication- and patient-related outcomes in Germany.

OBJECTIVE: To assess the effect of a routine medication review service in German community pharmacies (ATHINA) on drug-related problems (DRPs) and patient-related outcomes. MATERIALS AND METHODS: From 2015 to 2017, ATHINA patients were invited by their pharmacists to participate in a prospective, observational trial, meaning that they needed to attend to a follow-up visit (T2) 3 - 6 months after the routine ATHINA baseline (T0) and concluding visit (T1) to assess implementation rates of the pharmacists' interventions. Moreover, they were asked to fill in 2 surveys on drug treatment-related quality of life and satisfaction with the amount of information received about medicines at T0, T1, and T2. RESULTS: Of 132 recruited patients, 115 completed T2. At T0, pharmacists documented a DRP or information need for 114 of 115 patients. About half of these issues were resolved leading to 43/115 patients without any DRP or information need at T1 and 50/115 patients without any DRP or information need at T2 (i.e., absolute reduction by 42.6%, p < 0.001). Also, the number of patients who felt that their daily life was not impaired at all or only very slightly by their drug treatment increased from 54.7% (58/106) at T0 to 67.6% (73/108, p = 0.011) at T2. While the overall satisfaction score with the amount of information on medicines increased from 10.2 ± 5.5 at T0 over 14.6 ± 3.8 (T1) to 15.4 ± 3.1 (T2, p < 0.001), this increase did not correlate with reduced information needs. CONCLUSION: The results suggest that the intervention improves medication- and patient-related outcomes. However, causal relationships are still questionable.

Absolute Bioavailability of Microdosed Midazolam After Buccal Administration Is Dependent on Buccal Exposure Time.

Midazolam is an established probe drug to assess cytochrome P450 3A activity (phenotyping). Microdosed midazolam is increasingly used for this purpose; a buccal formulation might be of advantage, but buccal absorption might occur. We therefore tested in a single-center, open-label clinical trial with 12 healthy volunteers the absolute bioavailability of 10 µg of midazolam after buccal administration in relation to buccal exposure time. In relation to a drinking solution, there was an increase of midazolam exposure (area under the plasma concentration-time curve from time 0 to infinity) with increasing buccal exposure time with an apparent saturation at 100-second buccal exposure. Absolute bioavailability increased from 27.8% (95% confidence interval, 23.5-32.9) for the drinking solution (0 seconds) to 66.1% (95% confidence interval, 60.0-72.8) after 100-second buccal exposure with no further increase after 150 seconds. A Hill equation described the time dependency of midazolam bioavailability with maximal bioavailability as 64.5% and buccal exposure time resulting in half maximal bioavailability increase as 16 seconds. In conclusion, midazolam bioavailability is highly dependent on buccal exposure time, and even a few seconds of buccal exposure will increase bioavailability due to buccal absorption. This needs to be taken into account for any buccal administration of midazolam.

Pain severity and analgesics use in the community-dwelling older population: a drug utilization study from Germany.

PURPOSE: Chronic pain is common in the older population and a significant public health concern. However, comprehensive studies on analgesics use in this age group from Germany are scarce. This study aims to give a comprehensive overview on the use of the most common therapeutic groups of analgesics in community-dwelling older adults from Germany. METHODS: A cross-sectional study was carried out using data from a German cohort of 2038 community-dwelling adults aged 63-89 years. Descriptive statistics and logistic regression models were applied to assess the utilization of analgesics by age, sex, pain severity, pain duration, and locations. RESULTS: One out of four study participants was suffering from high-intensity or disabling pain. Approximately half of those taking analgesics still reported to suffer from high-intensity or disabling pain. Among analgesics users, occasional non-steroidal anti-inflammatory drugs (NSAIDs) use was the most frequent pain therapy (in 43.6% of users), followed by metamizole (dipyrone) use (16.1%), regular NSAIDs use (12.9%), strong opioids use (12.7%), and weak opioids use (12.0%). In multivariate logistic regression models, higher age, higher pain severity, longer pain duration, abdominal pain, and back pain were statistically significantly associated with opioids use. Metamizole use was also statistically significantly associated with higher pain severity but inversely associated with pain duration. CONCLUSIONS: A significant number of older German adults are affected by high-intensity and disabling chronic pain despite receiving analgesics. Long-term studies are needed to compare the effectiveness and safety of different treatments for chronic pain in older adults.

An Electronic Medication Module to Improve Health Literacy in Patients With Type 2 Diabetes Mellitus: Pilot Randomized Controlled Trial.

BACKGROUND: In primary care, patients play a crucial role in managing care processes and handling drug treatment. A decisive factor for success is their health literacy, and several interventions have been introduced to support patients in fulfilling their responsibility. OBJECTIVE: The aim of this study is to assess the influence of such an intervention (ie, a medication module) within a patient-led electronic health record on patients' health literacy. METHODS: We conducted a randomized controlled study among community-dwelling patients with type 2 diabetes mellitus. Patients were recruited from primary care practices. After randomization, patients either had access to an internet-based medication module allowing them to store their medication information, look up drug information, and print a medication schedule (intervention group), or they received an information brochure on the importance of medication schedules (control group). After 4-8 weeks, all patients were invited to attend a structured medication review (ie, follow-up visit). Data were collected via questionnaires before the start of the intervention and during the follow-up visit. The main outcome measure was the mean difference in health literacy between baseline and follow-up assessments of patients in the control and intervention groups. RESULTS: Of 116 recruited patients, 107 (92.2%) completed the follow-up assessment and were eligible for intention-to-treat analyses. Only 73 patients, of which 29 were in the intervention group, followed the study protocol and were eligible for per-protocol analysis. No differences in overall health literacy were observed in either the intention-to-treat or in the per-protocol cohorts. Reasons for a null effect might be that the cohort was not particularly enriched with participants with low health literacy, thus precluding measurable improvement (ie, ceiling effect). Moreover, the success of implementation was considered poor because both the correct application of the study procedure (ie, randomization according to the protocol and dropout of 29 patients) and the actual interaction with the medication module was modest (ie, dropout of 9 patients). CONCLUSIONS: The conduct of this randomized controlled study was challenging, leaving it open whether inadequate implementation, too short of a duration, or insufficient efficacy of the intervention, as such, contributed to the null effect of this study. This clearly outlines the value of piloting complex interventions and the accompanying process evaluations.

Medication beliefs and use of medication lists - is there a connection? Results from a before-and-after study in Germany.

BACKGROUND: Despite increasing digitalisation the paper-based medication list remains one of the most important instruments for the documentation and exchange of medication-related information. However, even elderly patients with polypharmacy who are at high risk for medication errors and adverse drug events, frequently do not receive or use a complete and comprehensible medication list. Increasing the use of medication lists would be a great contribution to medication safety and facilitate the work of health care providers. METHODS: This study is related to the project MeinPlan (MyPlan) which comprised an information campaign on safe drug administration in the Rhine-Neckar region in South Germany. The campaign was evaluated in a before-and-after study based on a survey among two independent, representative samples of citizens over 65 years. In total, 5034 questionnaires were analysed. While the effects of the primary outcome (the percentage of citizens using a medication list) have been reported elsewhere, this analysis focusses on the effects of the campaign on citizens' medication beliefs and assesses whether medication beliefs are associated with the use of medication lists, the use of over-the-counter drugs and the use of the tools offered by the campaign. Medication beliefs were assessed with the German version of the General Beliefs About Medicines Questionnaire (BMQ) which results in subscales for "General Overuse", "General Usefulness" and "General Harm". The use of medication lists and over-the-counter drugs was assessed with self-developed questionnaire items. RESULTS: No statistically significant change in citizens' medication beliefs before and after the campaign could be detected. Likewise, no association between medication beliefs and the use of medication lists, the use of over-the-counter drugs or the use of the tools offered by the campaign could be shown. CONCLUSIONS: A campaign focussing on the risks of drug administration did not change the medication beliefs of the targeted population. Moreover, citizens' general medication beliefs do not seem to be crucial for their decision to use a medication list or over-the-counter drugs. Strategies to improve the use of medication lists by patients should focus on other influential factors, such as individual benefits and barriers and socio-psychological factors.