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.

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.

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.

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.

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.

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.

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).

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.

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

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).

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

Nobiletin, sinensetin, and tangeretin are the main perpetrators in clementines provoking food-drug interactions in vitro.

For clementine juice, previous data indicate a possible food-drug interaction with substrates of key enzymes responsible for drug metabolism (i.e. cytochrome P450 [CYP] 3A4, CYP1A2).

Longitudinal association between panic disorder and health care costs in older adults.

Background: To analyze whether probable panic disorder (PD) is associated with health care costs in older age over time.

Methods: Data regarding individuals aged 65 and over were derived from two waves of the ESTHER cohort study (n  = 2,348, n  = 2,090). Probable PD was assessed using the panic screening module from the Patient Health Questionnaire.

Microdosed midazolam for the determination of cytochrome P450 3A activity: Development and clinical evaluation of a buccal film.

Cytochrome P450 3A (CYP3A) isozymes metabolize about 50% of all marketed drugs. Their activity can be modulated up to 400-fold, which has great impact on individual dose requirements for CYP3A substrates. The activity of CYP3A can be monitored using the CYP3A substrate midazolam.

Structure and Content of Drug Monitoring Advices Included in Discharge Letters at Interfaces of Care: Exploratory Analysis Preceding Database Development.

Background: Inadequate drug monitoring of drug therapy after hospital discharge facilitates adverse drug events and preventable hospital readmissions.

Objective: This study aimed to analyze the structure and content of drug monitoring advices of a representative sample of discharge letters as a basis for future electronic information systems.

Methods: On 2 days in November 2016, all discharge letters of 3 departments of a university hospital were extracted from the hospital information system.

A follow-up report on potential drug interactions with clementines: Two single case experiments show no effect on CYP3A-dependent midazolam clearance.

We have previously demonstrated that clementines have in vitro drug interaction potential. To assess the clinical relevance of clementine-drug interaction, two single case experiments with repetitive phenotyping of CYP3A activity were conducted. Although an increment of 43% in the estimated midazolam clearance (eCL) was observed during the first experiment in a renal transplant patient on tacrolimus after 4-d consumption of clementines (1 kg/d), and an increment of +89% of eCL was observed during chronic consumption of clementine juice in a healthy male volunteer, these changes lie within the range of intra-individual variability.