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.

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.

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.

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.

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.

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.

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 (nt1 = 2,348, nt2 = 2,090). Probable PD was assessed using the panic screening module from the Patient Health Questionnaire. Health care costs were obtained through monetary valuation of self-reported health care use data. Fixed effects regressions analyzed the association between transitions in probable PD status and change in health care costs, while adjusting for potential confounders. RESULTS: On a descriptive level, study participants with a positive PD screening displayed higher three-month health care costs compared to those without (incremental costs: € 259 for t1 , € 1,544 for t2 ). Transitions in probable PD were associated with an approximate increase of 65% in outpatient health care costs (ß = 0.50, p < .05). There was no significant association between probable PD transition and change in any other cost category. CONCLUSIONS: Using longitudinal data, our results highlight the economic consequences of probable PD in older adults. Future research should address whether reducing PD in older adults may reduce the associated economic burden and analyze underlying mechanisms.

Prolyl Hydroxylase Inhibition Enhances Liver Regeneration Without Induction of Tumor Growth.

OBJECTIVE: We sought to assess whether pharmacological inhibition of hypoxia-inducible transcription factor (HIF)-prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3) is a suitable strategy to stimulate liver regeneration after partial hepatectomy for colorectal liver metastases (CRLM). BACKGROUND: Liver regeneration occurs in a hypoxic environment. PHD1 to PHD3 are molecular oxygen sensors and increasingly considered as putative therapeutic targets. However, little is known about the effect of pharmacological PHD inhibition on tumor expansion, and on liver regeneration after surgical resection. METHODS: Various mouse models of liver regeneration after extended partial hepatectomy and portal vein ligation for multiple bilobar CRLM were applied to assess the effect of the small molecule pan-PHD inhibitor ethyl-3,4-dihydroxybenzoate (EDHB) on liver regeneration and metastatic tumor growth. Metabolism and biodistribution of EDHB were analyzed using liquid chromatography coupled to tandem mass spectrometry. RESULTS: EDHB selectively augmented liver regeneration after partial hepatectomy and portal vein ligation, and increased the expression of cell cycle-promoting cyclin proteins, without enhancing metastatic tumor growth. Systemically administered EDHB and its active metabolite 3,4-dihydroxybenzoic acid accumulated in the liver to selectively induce hepatoprotective effects in the liver, but not in tumor tissue, without humoral adverse effects. CONCLUSIONS: Pharmacological inhibition of PHDs using EDHB might represent a novel and safe strategy in the treatment of multiple bilobar CRLM.

Comparison of Nine Instruments to Calculate Anticholinergic Load in a Large Cohort of Older Outpatients: Association with Cognitive and Functional Decline, Falls, and Use of Laxatives.

OBJECTIVE: A patient's risk for anticholinergic adverse effects is frequently estimated by instruments evaluating the drugs included in his medication profile. It remains unknown, however, which characteristics should be included in such an assessment instrument aiming to reliably predict adverse anticholinergic outcomes. DESIGN: Cross-sectional study. SETTING: ESTHER cohort (Germany). PARTICIPANTS: Home-dwelling participants (N = 2,761) aged between 60 and 87 years. MEASUREMENTS: The association between anticholinergic load calculated with nine different instruments and four anticholinergic adverse outcomes was investigated in univariate and multivariate analyses. Therefore, linear models complemented with Kendall's tau rank correlation coefficients (ԏ) were applied for continuous outcomes and generalized linear models were used to derive odds ratios (ORs) with 95% confidence intervals (CIs) for binary endpoints. RESULTS: Based on the respective identification criteria for anticholinergic drugs, the nine instruments identified between 245 (9%) and 866 (31%) anticholinergic drug users (mean age ± SD: 73 ± 6 years; Mini-Mental State Examination [MMSE] score: 28.3 ± 2.07; Barthel Index: 97.1 ± 7.5; 291 reporting falls; 29 taking laxatives [surrogate for constipation]). In the multivariate analysis, only two instruments indicated a significant association between anticholinergic load and all four outcomes. The instrument considering the prescribed dose showed the strongest association with MMSE scores (ԏ = -0.10), falls (OR: 2.30; 95% CI: 1.50-3.52), and the use of laxatives (OR: 3.11; 95% CI: 1.04-9.36). CONCLUSIONS: Instruments most reliably predicted anticholinergicadverse events if they were either based on the drugs' serum anticholinergic activity and the suggestions of clinician experts or considered the actual prescribed dose.

Risk factors of adverse health outcomes after hospital discharge modifiable by clinical pharmacist interventions: a review with a systematic approach.

The present review assessed the evidence on risk factors for the occurrence of adverse health outcomes after discharge (i.e. unplanned readmission or adverse drug event after discharge) that are potentially modifiable by clinical pharmacist interventions. The findings were compared with patient characteristics reported in guidelines that supposedly indicate a high risk of drug-related problems. First, guidelines and risk assessment tools were searched for patient characteristics indicating a high risk of drug-related problems. Second, a systematic PubMed search was conducted to identify risk factors significantly associated with adverse health outcomes after discharge that are potentially modifiable by a clinical pharmacist intervention. After the PubMed search, 37 studies were included, reporting 16 risk factors. Only seven of 34 patient characteristics mentioned in pertinent guidelines corresponded to one of these risk factors. Diabetes mellitus (n = 11), chronic obstructive lung disease (n = 9), obesity (n = 7), smoking (n = 5) and polypharmacy (n = 5) were the risk factors reported most frequently in the studies. Additionally, single studies also found associations of adverse health outcomes with different drug classes {e.g. warfarin [hazard ratio 1.50; odds ratio (OR) 3.52], furosemide [OR 2.25] or high beta-blocker starting doses [OR 3.10]}. Although several modifiable risk factors were found, many patient characteristics supposedly indicating a high risk of drug-related problems were not part of the assessed risk factors in the context of an increased risk of adverse health outcomes after discharge. Therefore, an obligatory set of modifiable patient characteristics should be created and implemented in future studies investigating the risk for adverse health outcomes after discharge.

Desmethyl bosentan displays a similar in vitro interaction profile as bosentan.

The endothelin-1 receptor antagonists bosentan and ambrisentan used for the treatment of pulmonary arterial hypertension remarkably differ in their potential to act as perpetrators in pharmacokinetic drug-drug interactions. So far, it is not clear whether the metabolites of bosentan and ambrisentan contribute to the extent of drug interactions. We therefore investigated the effects of 4-hydroxymethyl ambrisentan, hydroxy bosentan, desmethyl bosentan, and hydroxy desmethyl bosentan on targets which are inhibited or induced by the parent compounds. The hydroxylated metabolites of ambrisentan and bosentan neither induced any of the genes investigated at the mRNA level, nor inhibited P-glycoprotein (P-gp) measured by calcein assay in L-MDR1 cells, and only weakly inhibited organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 measured by 8-fluorescein-cAMP uptake in HEK-OATP1B1 and HEK-OATP1B3 cells. In contrast, desmethyl bosentan induced mRNA expression of cytochrome P450 3A4 (CYP3A4, about 6-fold at 50 µM), ABCB1 (P-gp, about 4.5-fold at 50 µM), and ABCG2 (breast cancer resistance protein, about 2-fold at 50 µM), whereas CYP2C19, ABCB11, and ABCC2 (multidrug resistance-associated protein 2) were not induced in LS180 cells. In a reporter gene assay, desmethyl bosentan activated pregnane X receptor with the highest potency of all metabolites tested. Whereas desmethyl bosentan did not inhibit P-gp, it inhibited OATP1B1 with an IC50 of 3.8 µM (1.9-7.6) (geometric mean, 95% CI) and OATP1B3 with an IC50 of 7.4 µM (2.6-21.52). In conclusion, our data demonstrate that desmethyl bosentan exhibits a similar pharmacokinetic interaction profile as bosentan and might contribute to the inducing effects of the parent compound.

Characteristics of medication schedules used by elderly ambulatory patients.

PURPOSE: We investigated the prevalence and quality of medication schedules of elderly ambulatory patients and assessed factors associated with the availability of a medication schedule. In particular, we evaluated whether sending out a blank medication schedule template would increase the chances to use such a document. METHODS: Data originate from the ESTHER study, a cohort study conducted in Saarland, Germany, in which trained study physicians performed home visits. They scanned all medication schedules, recorded the participants' medication, and performed thorough geriatric assessments. As part of the intervention, a blank medication schedule template along with a brochure was mailed to half of the participants (intervention group) 4 weeks prior to the home visits. RESULTS: In total, 553 of 2470 participants (22.4 %) had a medication schedule. Almost two thirds of the schedules were issued by health care professionals (n = 353, 63.8 %). These schedules offered a higher quality, although important information such as over-the-counter (OTC) medication was regularly missing. Self-reported adherence was higher in participants who used self-issued medication schedules; however, self-reported medication adherence in patients with any medication schedule was poorer compared to those patients not using a schedule. Factors associated with the availability of a medication schedule were male sex, a higher number of medicines to take, and a more complex drug regimen. The intervention did not increase the number of patients having a medication schedule. CONCLUSION: Only a minority of elderly ambulatory patients had a medication schedule at home. Sending out a brochure along with a blank medication schedule template did not increase the prevalence of medication schedules.

Development and evaluation of an algorithm to facilitate drug prescription for inpatients with feeding tubes.

PURPOSE: We aimed to develop and evaluate an algorithm to facilitate drug switching between primary and tertiary care for patients with feeding tubes. METHODS: An expert consortium developed an algorithm and applied it manually to 267 preadmission drugs of 46 patients admitted to a surgical ward of a tertiary care university hospital between June 12 and December 2, 2013, and requiring a feeding tube during their inpatient stay. RESULTS: The new algorithm considered the following principles: Drugs should be ideally listed on the hospital drug formulary (HDF). Additionally, drugs should include the same ingredient instead of a therapeutic equivalent. Preferred dosage forms were appropriate liquids, followed by solid drugs with liquid administration form, and solid drugs that could be crushed and/or suspended. Of all evaluated drugs, 83.5% could be switched to suitable drugs listed on the HDF and another 6.0% to drugs available on the German drug market. Additionally, for 4.1% of the drugs, the integration of individual switching rules allowed the switch from enteric-coated to immediate-release drugs. Consequently, 6.4% of the drugs could not be automatically switched and required case-to-case decision by a clinical professional (e.g., from sustained-release to immediate-release). CONCLUSIONS: The predefined principles were successfully integrated in the new algorithm. Thus, the algorithm switched more than 90% of the evaluated preadmission drugs to suitable drugs for inpatients with feeding tubes. This finding suggests that the algorithm can readily be transferred to an electronic format and integrated into a clinical decision support system.

Health service use and costs associated with excess weight in older adults in Germany.

BACKGROUND: excess weight is a risk factor for numerous co-morbidities that predominantly occur in later life. This study's purpose was to analyse the association between excess weight and health service use/costs in the older population in Germany. METHODS: this cross-sectional analysis used data of n = 3,108 individuals aged 58-82 from a population-based prospective cohort study. Body mass index (BMI) and waist-to-height ratio (WHtR) were calculated based on clinical examinations. Health service use was measured by a questionnaire for a 3-month period. Corresponding costs were calculated applying a societal perspective. RESULTS: 21.8% of the sample were normal weight, 43.0% overweight, 25.5% obese class 1 and 9.6% obese class ≥2 according to BMI. In 42.6%, WHtR was ≥0.6. For normal weight, overweight, obese class 1 and obese class ≥2 individuals, mean costs (3-month period) of outpatient care were 384€, 435€, 475€ and 525€ (P < 0.001), mean costs of inpatient care were 284€, 408€, 333€ and 652€ (P = 0.070) and mean total costs 716€, 891€, 852€ and 1,244€ (P = 0.013). For individuals with WHtR <0.6 versus ≥0.6, outpatient costs were 401€ versus 499€ (P < 0.001), inpatient costs 315€ versus 480€ (P = 0.016) and total costs 755€ versus 1,041€ (P < 0.001). Multiple regression analyses controlling for sociodemographic variables showed a significant effect of obesity on costs of outpatient care (class 1: +72€; class ≥2: +153€) and total costs (class ≥2: +361€) while the effect of overweight was not significant. WHtR ≥0.6 significantly increased outpatient costs by +79€ and total costs by +189€. CONCLUSIONS: excess weight is associated with increased service use and cost in elderly individuals, in particular in obese class ≥2 individuals.

Pharmacokinetic interaction profile of riociguat, a new soluble guanylate cyclase stimulator, in vitro.

Riociguat is a new soluble guanylate cyclase stimulator under development for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. So far, the interaction potential of riociguat with other drugs is nearly unknown. Therefore, we assessed in vitro the potency of riociguat to inhibit important drug metabolising enzymes (cytochrome P450 (CYP) 3A4, CYP2C19, and CYP2D6) and drug transporters (P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and organic anion transporting polypeptides (OATP) 1B1 and 1B3). In addition we evaluated its substrate characteristics for P-gp, BCRP, and the multidrug resistance-associated protein 1 (MRP1/ABCC1). We also assessed riociguat's inducing properties on important drug metabolising enzymes and transporters and investigated its ability to activate the pregnane-X-receptor (PXR). Riociguat was identified as a weak to moderate inhibitor of P-gp (f2-value: 11.7 ± 4.8 µM), BCRP (IC50 = 46.2 ± 20.3 µM), OATP1B1 (IC50 = 34.1 ± 3.15 µM), OATP1B3 (IC50 = 50.3 ± 7.5 µM), CYP2D6 (IC50 = 12.4 ± 0.74 µM), and CYP2C19 (IC50 = 46.1 ± 7.14 µM). Furthermore, it induced mRNA expression of BCRP/ABCG2 (3-fold at 20 µM) and to a lesser extent of CYP3A4 (2.3-fold at 20 µM), UGT1A4, and ABCB11. The only weak inducing properties were confirmed by weak activation of PXR. Considering its systemic concentrations its interaction potential as a perpetrator drug seems to be low. In contrast, our data suggest that riociguat is a P-gp substrate and might therefore act as a victim drug when co-administered with strong P-gp inductors or inhibitors.

Pilot study to assess the influence of an enhanced medication plan on patient knowledge at hospital discharge.

PURPOSE: This study assessed the effect of providing an enhanced medication plan (EMP) to patients during patient-physician conversation at hospital discharge and evaluated its immediate impact on patient knowledge on pharmacotherapy. METHODS: We observed patient-physician conversations at hospital discharge in three internal medicine wards of the University Hospital Heidelberg before and after the EMP was integrated into the discharge process, and documented how and to what extent physicians provided the patients with drug information. After the conversation, the patients' knowledge was evaluated by three standardized questions about their pharmacotherapy. RESULTS: We observed 90 conversations (50 before EMP-implementation, 40 after). In both phases, the conversation duration was 5.6-6 min (p = 0.56). However, the time spent on drug information increased significantly by 61.7% after EMP-implementation (+63 s, p = 0.02). Before implementation, physicians gave at least one drug administration recommendation for 75.1% of all drugs, compared to 84.6% after implementation (p = 0.02). The EMP provided information for almost all drugs (98.9%; p < 0.01) after implementation. Three times more patients answered all questions correctly after EMP-implementation (p < 0.01). CONCLUSION: The provision of an EMP improves information transfer and therefore increases the patients' knowledge of their individual drug treatment without prolonging the overall discharge process.

Inappropriate crushing information on ward lists: cytotoxic drugs, capsules, and modified release formulations are gravely neglected.

PURPOSE: The aim of this study was to assess the quality of the information sources on the modification of solid medication dosage forms (crushing, suspending) used on the wards of a large university hospital in Germany. METHODS: We performed on-site visits of all 79 wards of the hospital and collected available sources of information on the modification of solid medication dosage forms. To evaluate the quality of such information, we gathered reference information for each listed brand from the respective pharmaceutical company, transferred this information to a knowledge base, and classified it into three categories, i.e., modification not allowed, modification allowed, and modification allowed under certain circumstances. RESULTS: Twenty-two lists of information on drug modification were identified in the 79 wards. Each list contained errors, and on average 17.0 % (range 8.0-32.3 %) of the brands listed had been withdrawn from the market or the information on crushing and/or suspending was inappropriate. Most of the incorrect information either concerned brands containing ingredients that were potentially hazardous to the staff members who prepared the drugs or referred to special dosage forms such as capsules and modified release formulations (e.g., cytotoxic drugs). CONCLUSION: We found that the lists posted on the wards were often outdated and did not take into account the limitations/problems of preparing drugs on the ward. Our results emphasize that lists posted in wards need to be checked regularly and that "ready-to-use" lists from third parties might require adaptation to site-specific conditions in order to protect healthcare staff from exposure to potentially hazardous drugs during drug preparation and ensure safe drug application to the patient.

Health care costs in the elderly in Germany: an analysis applying Andersen's behavioral model of health care utilization.

BACKGROUND: To analyze the association of health care costs with predisposing, enabling, and need factors, as defined by Andersen's behavioral model of health care utilization, in the German elderly population. METHODS: Using a cross-sectional design, cost data of 3,124 participants aged 57-84 years in the 8-year-follow-up of the ESTHER cohort study were analyzed. Health care utilization in a 3-month period was assessed retrospectively through an interview conducted by trained study physicians at respondents' homes. Unit costs were applied to calculate health care costs from the societal perspective. Socio-demographic and health-related variables were categorized as predisposing, enabling, or need factors as defined by the Andersen model. Multimorbidity was measured by the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Mental health status was measured by the SF-12 mental component summary (MCS) score. Sector-specific costs were analyzed by means of multiple Tobit regression models. RESULTS: Mean total costs per respondent were 889 € for the 3-month period. The CIRS-G score and the SF-12 MCS score representing the need factor in the Andersen model were consistently associated with total, inpatient, outpatient and nursing costs. Among the predisposing factors, age was positively associated with outpatient costs, nursing costs, and total costs, and the BMI was associated with outpatient costs. CONCLUSIONS: Multimorbidity and mental health status, both reflecting the need factor in the Andersen model, were the dominant predictors of health care costs. Predisposing and enabling factors had comparatively little impact on health care costs, possibly due to the characteristics of the German social health insurance system. Overall, the variables used in the Andersen model explained only little of the total variance in health care costs.

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.