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Hintergrund: Medikamente mit anticholinergen (ACh) Nebenwirkungen sind mit vielfältigen negativen Outcomes (z.B. Stürze) assoziiert. Existierende Instrumente zur Erhebung der anticholinergen Belastung sind heterogen, inkonsistent in der Bewertung einzelner Wirkstoffe, berücksichtigen [zum vollständigen Text gelangen Sie über die oben angegebene URL]

Andreas D Meid,1 Carmen Ruff,1 Lucas Wirbka,1 Felicitas Stoll,1 Hanna M Seidling,1,2 Andreas Groll,3 Walter E Haefeli1,2 1Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg 69120, Germany; 2Cooperation Unit Clinical Pharmacy, University of Heidelberg, Heidelberg 69120, Germany; 3Department of Statistics, TU Dortmund University, Dortmund 44227, GermanyCorrespondence: Andreas D MeidDepartment of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg 69120, GermanyTel +49 6221 56 37113Fax +49 6221 56 4642Email Andreas.Meid@med.uni-heidelberg.deAbstract: When healthcare professionals have the choice between several drug treatments for their patients, they often experience considerable decision uncertainty because many decisions simply have no single “best” choice. The challenges are manifold and include that guideline recommendations focus on randomized controlled trials whose populations do not necessarily correspond to specific patients in everyday treatment. Further reasons may be insufficient evidence on outcomes, lack of direct comparison of distinct options, and the need to individually balance benefits and risks. All these situations will occur in routine care, its outcomes will be mirrored in routine data, and could thus be used to guide decisions. We propose a concept to facilitate decision-making by exploiting this wealth of information. Our working example for illustration assumes that the response to a particular (drug) treatment can substantially differ between individual patients depending on their characteristics (heterogeneous treatment effects, HTE), and that decisions will be more precise if they are based on real-world evidence of HTE considering this information. However, such methods must account for confounding by indication and effect measure modification, eg, by adequately using machine learning methods or parametric regressions to estimate individual responses to pharmacological treatments. The better a model assesses the underlying HTE, the more accurate are predicted probabilities of treatment response. After probabilities for treatment-related benefit and harm have been calculated, decision rules can be applied and patient preferences can be considered to provide individual recommendations. Emulated trials in observational data are a straightforward technique to predict the effects of such decision rules when applied in routine care. Prediction-based decision rules from routine data have the potential to efficiently supplement clinical guidelines and support healthcare professionals in creating personalized treatment plans using decision support tools.Keywords: claims data, decision-making, heterogeneous treatment effects, effect modification, confounding by indication, prediction-based decision rules

Purpose The aim of this systematic review was to identify methods used to assess medication preferences in older adults and evaluate their advantages and disadvantages with respect to their applicability to the context of multimorbidity and polypharmacy. Material and Methods Three electronic databases (PubMed, Web of Science, PsycINFO) were searched. Eligible studies elicited individual treatment or outcome preferences in a context that involved long-term pharmacological treatment options. We included studies with a study population aged ≥ 65 years and/or with a mean or median age of ≥ 75 years. Qualitative studies, studies assessing preferences for only two different treatments, and studies targeting preferences for life-sustaining treatments were excluded. The identified preference measurement methods were evaluated based on four criteria (time budget, cognitive demand, variety of pharmacological aspects, and link with treatment strategies) judged to be relevant for the elicitation of patient preferences in polypharmacy. Results Sixty articles met the eligibility criteria and were included in the narrative synthesis. Fifty-five different instruments to assess patient preferences, based on 24 different elicitation methods, were identified. The most commonly applied preference measurement techniques were “medication willingness” (description of a specific medication with inquiry of the participant’s willingness to take it), discrete choice experiments, Likert scale-based questionnaires, and rank prioritization. The majority of the instruments were created for disease-specific or context-specific settings. Only three instruments (Outcome Prioritization Tool, a complex intervention, “MediMol” questionnaire) dealt with the broader issue of geriatric multimorbidity. Only seven of the identified tools showed somewhat favorable characteristics for a potential use of the respective method in the context of polypharmacy. Conclusion Up to now, few instruments have been specifically designed for the assessment of medication preferences in older patients with multimorbidity. To facilitate valid preference elicitation in the context of geriatric polypharmacy, future research should focus on suitable characteristics of existing techniques to develop new measurement approaches for this increasingly relevant population.

Additional file 2. Overview of the optimization measures that were considered as helpful for data analysis. The complexity factors identified as relevant for patients, thus leading to the proposal of optimization measures, and a description of the optimization measures suggested by the tool are given.

Additional file 1. Histograms that show the distribution of the number of complexity factors and the number of drugs among all three study groups.

Additional file 2

Additional file 1

Targeting dementia prevention, first trials addressing multiple modifiable risk factors showed promising results in at-risk populations. In Germany, AgeWell.de is the first large-scale initiative investigating the effectiveness of a multi-component lifestyle intervention against cognitive decline. We aimed to investigate the recruitment process and baseline characteristics of the AgeWell.de participants to gain an understanding of the at-risk population and who engages in the intervention. General practitioners across five study sites recruited participants (aged 60&ndash, 77 years, Cardiovascular Risk Factors, Aging, and Incidence of Dementia/CAIDE dementia risk score &ge, 9). Structured face-to-face interviews were conducted with eligible participants, including neuropsychological assessments. We analyzed group differences between (1) eligible vs. non-eligible participants, (2) participants vs. non-participants, and (3) between intervention groups. Of 1176 eligible participants, 146 (12.5%) dropped out before baseline, the study population was thus 1030 individuals. Non-participants did not differ from participants in key sociodemographic factors and dementia risk. Study participants were M = 69.0 (SD = 4.9) years old, and 52.1% were women. The average Montreal Cognitive Assessment/MoCA score was 24.5 (SD = 3.1), indicating a rather mildly cognitively impaired study population, however, 39.4% scored &ge, 26, thus being cognitively unimpaired. The bandwidth of cognitive states bears the interesting potential for differential trial outcome analyses. However, trial conduction is impacted by the COVID-19 pandemic, requiring adjustments to the study protocol with yet unclear methodological consequences.

Supplemental material, sj-pdf-1-mdm-10.1177_0272989X211064604 for Can Machine Learning from Real-World Data Support Drug Treatment Decisions? A Prediction Modeling Case for Direct Oral Anticoagulants by Andreas D. Meid, Lucas Wirbka, Andreas Groll and Walter E. Haefeli in Medical Decision Making

Background The increasing complexity of current drug therapies jeopardizes patient adherence. While individual needs to simplify a medication regimen vary from patient to patient, a straightforward approach to integrate the patients’ perspective into decision making for complexity reduction is still lacking. We therefore aimed to develop an electronic, algorithm-based tool that analyses complexity of drug treatment and supports the assessment and consideration of patient preferences and needs regarding the reduction of complexity of drug treatment. Methods Complexity factors were selected based on literature and expert rating and specified for integration in the automated assessment. Subsequently, distinct key questions were phrased and allocated to each complexity factor to guide conversation with the patient and personalize the results of the automated assessment. Furthermore, each complexity factor was complemented with a potential optimisation measure to facilitate drug treatment (e.g. a patient leaflet). Complexity factors, key questions, and optimisation strategies were technically realized as tablet computer-based application, tested, and adapted iteratively until no further technical or content-related errors occurred. Results In total, 61 complexity factors referring to the dosage form, the dosage scheme, additional instructions, the patient, the product, and the process were considered relevant for inclusion in the tool; 38 of them allowed for automated detection. In total, 52 complexity factors were complemented with at least one key question for preference assessment and at least one optimisation measure. These measures included 29 recommendations for action for the health care provider (e.g. to suggest a dosage aid), 27 training videos, 44 patient leaflets, and 5 algorithms to select and suggest alternative drugs. Conclusions Both the set-up of an algorithm and its technical realisation as computer-based app was successful. The electronic tool covers a wide range of different factors that potentially increase the complexity of drug treatment. For the majority of factors, simple key questions could be phrased to include the patients’ perspective, and, even more important, for each complexity factor, specific measures to mitigate or reduce complexity could be defined.

Background Ambrisentan is a selective endothelin receptor antagonist used for the treatment of pulmonary arterial hypertension (PAH). Little is known about ambrisentan removal by hemodialysis in patients with end-stage renal disease (ESRD). Case presentation A 53-year-old woman with HIV/hepatitis C virus (HCV) co-infection, PAH and ESRD on regular hemodialyis was admitted in our hospital due to refractory heart failure while on treatment with bosentan (125 mg twice daily) and tadalafil (20 mg once daily) for PAH and antiretroviral treatment (cART) including darunavir/cobicistat (800/150 mg once daily). Excessive exposure to bosentan due to drug interactions between bosentan and darunavir/cobicistat was suspected. Bosentan was replaced by ambrisentan, with progressive improvement in her clinical condition. Pre- and postdialyzer cocentrations of ambrisentan in plasma were determined and hemodialysis extraction ratio for ambrisentan was 2%. Conclusions Our results suggest that hemodialysis results in minimal ambrisentan removal, and therefore no specific ambrisentan dosage adjustment seems to be required in ESRD patients undergoing hemodialysis.

Background/research question: Multimorbidity and inappropriate polypharmacy are common in older patients and may lead to medication-related harm resulting in hospitalization and worsening of health-related quality of life (HRQoL). Considering the complex interplay between conditions and medications[for full text, please go to the a.m. URL], EbM und Digitale Transformation in der Medizin; 20. Jahrestagung des Deutschen Netzwerks Evidenzbasierte Medizin

Background In the absence of treatment options, the WHO emphasizes the identification of effective prevention strategies as a key element to counteract the dementia epidemic. Regarding the complex nature of dementia, trials simultaneously targeting multiple risk factors should be particularly effective for prevention. So far, however, only few such multi-component trials have been launched, but yielding promising results. In Germany, comparable initiatives are lacking, and translation of these complex interventions into routine care was not yet done. Therefore, AgeWell.de will be conducted as the first multi-component prevention trial in Germany which is closely linked to the primary care setting. Methods AgeWell.de will be designed as a multi-centric, cluster-randomized controlled multi-component prevention trial. Participants will be older community-dwelling general practitioner (GP) patients (60–77 years; n = 1,152) with increased dementia risk according to CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) Dementia Risk Score. Recruitment will take place at 5 study sites across Germany. GP practices will be randomized to either intervention A (advanced) or B (basic). GPs will be blinded to their respective group assignment, as will be the statistician conducting the randomization. The multi-component intervention (A) includes nutritional counseling, physical activity, cognitive training, optimization of medication, management of vascular risk factors, social activity, and, if necessary, further specific interventions targeting grief and depression. Intervention B includes general health advice on the intervention components and GP treatment as usual. We hypothesize that over the 2-year follow-up period the intervention group A will benefit significantly from the intervention program in terms of preserved cognitive function/delayed cognitive decline (primary outcome), and other relevant (secondary) outcomes (e.g. quality of life, social activities, depressive symptomatology, cost-effectiveness). Discussion AgeWell.de will be the first multi-component trial targeting risk of cognitive decline in older adults in Germany. Compared to previous trials, AgeWell.de covers an even broader set of interventions suggested to be beneficial for the intended outcomes. The findings will add substantial knowledge on modifiable lifestyle factors to prevent or delay cognitive decline. Trial registration German Clinical Trials Register (reference number: DRKS00013555).

Marcel KP Kusch,1,2 Walter E Haefeli,1,2 Hanna M Seidling1,2 1Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, 69120 Heidelberg, Baden-Wurttemberg, Germany; 2Cooperation Unit Clinical Pharmacy, University of Heidelberg, 69120 Heidelberg, Baden-Wurttemberg, Germany Purpose: The aim of this study was to 1) describe drug information desired by patients and 2) analyze how such information could be customized to be presented to patients according to their individual information needs.Materials and methods: We performed a scoping literature search and identified relevant drug information topics by assessing and clustering 1) studies analyzing patients’ enquiries to drug information hotlines and services, and 2) qualitative studies evaluating patient drug information needs. For the two most frequently mentioned topics, we further analyzed which components (ie, information domains) the topics contained and examined patients’ and health care professionals’ (HCPs) views on these components.Results: Of 27 identified drug information topics in the literature search, patients most frequently requested information on adverse drug reactions (ADRs) and drug–drug interactions (DDIs). Hypothetically, those topics are composed of seven distinct information domains each (eg, ADR and DDI classification by frequency, severity, or onset; information on management strategies, monitoring, and prevention strategies). Patients’ and HCPs’ appraisal concerning the information content of these domains varies greatly and is even lacking sometimes.Conclusion: Patients particularly request information on ADRs and DDIs. Approaches to customize such information are sparse. The identified information domains of each topic could be used to structure corresponding drug information and to thus facilitate customization to individual information needs. Keywords: medication information, information needs, customization, adverse drug reactions, side effects, drug–drug interactions&nbsp

A large body of evidence suggests that not only direct anticoagulant effects but also major bleeding events and stroke prevention depend on plasma concentrations of direct oral anticoagulants (DOACs). Concomitant drugs that cause drug-drug interactions (DDIs) alter DOAC exposure by increasing or decreasing DOAC bioavailability and/or clearance; hence, they might affect the efficacy and safety of DOAC therapy. Patients with renal impairment already receive smaller DOAC maintenance doses because avoidance of elevated DOAC exposure might prevent serious bleeding events. For other causes of increased exposure such as DDIs, management is often less well-defined. Considering that DOAC patients are often older and have multiple co-morbidities, polypharmacy is highly prevalent. However, the effect of multiple drugs on DOAC exposure, and especially the impact of DDIs when concurring with drug-disease interactions as observed in renal impairment, has not been thoroughly elucidated. In order to provide effective and safe anticoagulation with DOACs, understanding the mechanisms and magnitude of DDIs appears relevant. Instead of avoiding drug combinations with DOACs, more DDI trials should be conducted and new strategies such as dose adjustments based on therapeutic drug monitoring should be investigated. However, dose adjustments based on concentration measurements cannot currently be recommended because evidence-based data are missing.

Objectives: The detrimental haemodynamic changes observed in septicaemia are generalised vasodilation, arterial hypotension, and hyporesponsiveness to vasopressor compounds, all of which could be explained by the release of an endogenous vasodilator. Experimental and clinical evidence suggests that tumour necrosis factor-α (TNF) induces the expression of vascular nitric oxide (NO) synthase within hours and that NO released from smooth muscle cells could be involved in the pathogenesis of septic shock. The aim of this study was to investigate the role of NO in the vascular effects of TNF. Methods: Using the dorsal hand vein compliance technique, the effect of the NO synthase inhibitor L-NG-monomethyl-arginine (L-NMMA) on α1-adrenergic responsiveness (phenylephrine 1.25-8000 ng/min) was studied after prolonged local venous infusion of TNF (8.7 μg in 5 h) in 9 volunteers and in 6 volunteers without previous cytokine exposure. Results: Mean (±s.e.) maximum phenylephrine constriction (Emax) was 73 ± 6% and log dose-rates exerting 50% of Emax (log ED50) were 3.2 ± 0.09 (geometric mean: 1535 ng/min). Local co-administration of L-NMMA at a dose sufficiently high to block NO formation (3.4 μmol/min) increased venous sensitivity to phenylephrine threefold (log ED50 2.8 ± 0.1, P < 0.015; geometric mean: 574 ng/min) whereas Emax was similar (73 ± 5%). In the controls the phenylephrine dose-response relationship remained unaffected by simultaneous administration of L-NMMA. Conclusions: As no basal release of NO occurs in hand veins without previous exposure to TNF these results provide direct evidence for induction of NO formation in the human vasculature and consecutive resistance to α-adrenergic venoconstriction. NO might, therefore, be a key mediator of haemodynamic impairment in humans under conditions with known elevations of circulating TNF, such as a septic shock

Introduction: Hypoxia and increased stabilization of hypoxia inducible factors (HIF-1 and -2) are common in a variety of tumors, and associated with increased tumor invasiveness and metastasis. On the other hand, HIF prolyl-hydroxylase (PHD) enzymes are putative pharmacological targets for enhancing[for full text, please go to the a.m. URL], 132. Kongress der Deutschen Gesellschaft für Chirurgie

We aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam.In an open, one sequence, crossover study, 16 healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg oral) and regular milligram (1 mg intravenous and 3 mg oral) doses to assess the linearity of plasma and urine pharmacokinetics.Dose-normalized AUC and Cmax were 37.1 ng ml(-1 ) h [95% CI 35.5, 40.6] and 39.1 ng ml(-1) [95% CI 30.4, 50.2] for the microdose and 39.0 ng ml(-1 ) h [95% CI 36.1, 42.1] and 37.1 ng ml(-1) [95% CI 26.9, 51.3] for the milligram dose. CLmet was 253 ml min(-1) [95% CI 201, 318] vs. 278 ml min(-1) [95% CI 248, 311] for intravenous doses and 1880 ml min(-1) [95% CI 1590, 2230] vs. 2050 ml min(-1) [95% CI 1720, 2450] for oral doses. Oral bioavailability of a midazolam microdose was 23.4% [95% CI 20.0, 27.3] vs. 20.9% [95% CI 17.1, 25.5] after the regular dose. Hepatic and gut extraction ratios for microgram doses were 0.44 [95% CI 0.39, 0.49] and 0.53 [95% CI 0.45, 0.63] and compared well with those for milligram doses (0.43 [95% CI 0.37, 0.49] and 0.61 [95% CI 0.53, 0.70]).The pharmacokinetics of an intravenous midazolam microdose is linear to the applied regular doses and can be used to assess safely systemic CYP3A activity and, in combination with oral microdoses, pre-systemic CYP3A activity.

Informationstechnologie (IT) im Gesundheitswesen hat nachweislich das Potential, die Qualität und Effizienz der Gesundheitsversorgung zu verbessern. Dies gilt insbesondere für den Einsatz von IT im Bereich der Arzneimitteltherapiesicherheit (AMTS-IT). Gleichzeitig gibt es Studien, welche auf mögliche Komplikationen und daraus resultierenden Gefährdungen der Patientensicherheit hinweisen, wenn AMTS-IT auf unangemessene Weise entwickelt, eingeführt oder genutzt wird. Das vorliegende Memorandum hat das Ziel, für Entscheidungsträger und Fachleute wesentliche Definitionen und Beobachtungen zu AMTS-IT zusammenzufassen und daraus Handlungsempfehlungen abzuleiten, die auch auf den weiteren Forschungsbedarf verweisen. Die Empfehlungen adressieren unter anderem eine stufenweise, umfassende AMTS-Strategie, die Integration von AMTS-IT in klinische Systeme und die Verzahnung von Kontextinformation in alle Prüfungen, die Einbeziehung der Patienten, die Berücksichtigung einer semantischen Integration von Informationsressourcen, die Benutzerfreundlichkeit und Adaptierbarkeit von AMTS-IT und die Notwendigkeit ihrer kontinuierlichen Evaluierung., GMS Medizinische Informatik, Biometrie und Epidemiologie; 10(1):Doc03; ISSN 1860-9171

Background: Proton pump inhibitors (PPI) are used to treat peptic disorders, like gastro-esophageal disease (GERD) and ulcer, but non-responder patients refractory to PPI treatment are very common [ref:1]. An activation of the gastric H+/K+-ATPase (proton pump) is necessary [for full text, please go to the a.m. URL], 20. Jahrestagung der Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie

We aimed to develop a generic knowledge base with drug administration recommendations which allows the generation of a dynamic and comprehensive medication plan and to evaluate its comprehensibility and potential benefit in a qualitative pilot study with patients and physicians.Based on a literature search and previously published medication plans, a prototype was developed and iteratively refined through qualitative evaluation (interviews with patients and focus group discussions with physicians). To develop the recommendations for safe administration of specific drugs we screened the summary of product characteristics (SmPC) of different exemplary brands, allocated the generated advice to groups with brands potentially requiring the same advice, and reviewed these allocations regarding applicability and appropriateness of the recommendations.For the recommendations, 411 SmPCs of 140 different active ingredients including all available galenic formulations, routes of administrations except infusions, and administration devices were screened. Finally, 515 distinct administration recommendations were included in the database. In 926 different generic groups, 29,879 allocations of brands to general advice, food advice, indications, step-by-step instructions, or combinations thereof were made. Thereby, 27,216 of the preselected allocations (91.1%) were confirmed as appropriate. In total, one third of the German drug market was labelled with information.Generic grouping of brands according to their active ingredient and other drug characteristics and allocation of standardized administration recommendations is feasible for a large drug market and can be integrated in a medication plan.

The aim of this study was to assess the effect of the cytochrome P450 (CYP) 3A4 and organic anion-transporting polypeptide (OATP) 1B1 inhibitor clarithromycin on the pharmacokinetics of bosentan. We also aimed to evaluate the impact of CYP2C9 and SLCO1B1 (encoding for OATP1B1) genotypes and their combination.We assessed the effect of the OATP and CYP3A inhibitor clarithromycin on bosentan pharmacokinetics at steady state and concurrently quantified changes of CYP3A activity using midazolam as a probe drug. Sixteen healthy volunteers received therapeutic doses of bosentan (125 mg twice daily) for 14 days and clarithromycin (500 mg twice daily) concomitantly for the last 4 days, and bosentan pharmacokinetics was assessed on days 1, 10 and 14.Clarithromycin significantly increased bosentan area under the plasma concentration-time curve of the dosing interval 3.7-fold and peak concentration 3.8-fold in all participants irrespective of the genotype. Clarithromycin also reduced CYP3A activity (midazolam clearance) in all participants; however, these changes were not correlated to the changes of bosentan clearance.Clarithromycin substantially increases the exposure to bosentan, suggesting that dose reductions may be necessary.

Metformin pharmacokinetics depends on the presence and activity of membrane-bound drug transporters and may be affected by transport inhibitors. The aim of this study was to investigate the effects of trimethoprim on metformin pharmacokinetics and genetic modulation by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1) polymorphisms.Twenty-four healthy volunteers received metformin 500 mg three times daily for 10 days and trimethoprim 200 mg twice daily from day 5 to 10. Effects of trimethoprim on steady-state metformin pharmacokinetics were analysed.In the population as a whole, trimethoprim significantly reduced the apparent systemic metformin clearance (CL/F) from 74 to 54 l h(-1) and renal metformin clearance from 31 to 21 l h(-1) , and prolonged half-life from 2.7 to 3.6 h (all P0.01). This resulted in an increase in the maximal plasma concentration by 38% and in the area under the plasma concentration-time curve by 37%. In volunteers polymorphic for both OCT2 and MATE1, trimethoprim had no relevant inhibitory effects on metformin kinetics. Trimethoprim was associated with a decrease in creatinine clearance from 133 to 106 ml min(-1) (P0.01) and an increase in plasma lactate from 0.94 to 1.2 mmol l(-1) (P = 0.016).The extent of inhibition by trimethoprim was moderate, but might be clinically relevant in patients with borderline renal function or high-dose metformin.

Hintergrund: Um den Gesundheitsstatus einer Population zu beschreiben und gesundheitsrelevante Endpunkte vorauszusagen, müssen chronischen Erkrankungen erfasst und gewichtet werden. Medikationsbezogene Multimorbiditäts-Scores haben den Vorteil, dass sie auch dann anwendbar sind, wenn Diagn[for full text, please go to the a.m. URL], 10. Deutscher Kongress für Versorgungsforschung; 18. GAA-Jahrestagung

Hintergrund: Komplexe Interventionen sind weit verbreitet. Zu deren Entwicklung und Evaluation wurde vom Medical Research Council (UK) ein Framework zum Vorgehen bei Entwicklung, Machbarkeitsprüfung, Hauptstudie und Implementierung vorgeschlagen. In der PRIMUM-Studie (BMBF Fkz: 01GK0702) wurde [for full text, please go to the a.m. URL], EbM – ein Gewinn für die Arzt-Patient-Beziehung?; Forum Medizin 21 der Paracelsus Medizinischen Privatuniversität & 11. EbM-Jahrestagung des Deutschen Netzwerks Evidenzbasierte Medizin

To determine how concomitant use of potentially interacting drugs, drug dosage, and duration of therapy modify the risk of hip fracture associated with use of benzodiazepines and benzodiazepine-related drugs (BDZ) in older adults.A nested case-control study was conducted in Medicare patients 65 years or older, enrolled in the Pennsylvania drug assistance program (PACE) between 1994 and 2005. We included 17,198 patients with a hip fracture leading to hospitalization and 85,990 controls matched on hospitalization (index date). BDZ and interacting drug use within 2 weeks preceding the index date was determined using information on date of drug dispensing, days supplied, quantity dispensed, and strength. Date of the first BDZ prescription within the year preceding the index date was used as surrogate for duration of therapy.While the adjusted relative risk (RR) for overall BDZ use and hip fracture was 1.2 (95% confidence interval 1.1, 1.2), the RRs for concomitant use of alprazolam, lorazepam, and zolpidem and their interacting drugs were 1.5 (1.3, 1.7), 1.9 (1.7, 2.2), and 1.7 (1.4, 2.0), and 2.1 (1.5, 2.8) for BDZ use initiated within 14 days preceding the index date. RR increased with increasing BDZ dose and was highest for defined daily BDZ doses1 [RR: 1.3 (1.2, 1.5)].BDZ associated hip fracture risk increases with concomitant use of interacting drugs, higher doses, and is highest at initiation. Clinicians should avoid concomitant use of BDZ and interacting drugs, because their impact on hip fracture risk is at least additive.

Einleitung: Aus gesundheitsökonomischer Sicht ist es sinnvoll, bei der Arzneimittelverordnung auf preisgünstige Alternativen (z.B. Generika statt Originalpräparate) zurückzugreifen [ref:1]. Daher besteht die gesetzliche Anforderung an Verordnungssoftware im vertragsärztlichen[for full text, please go to the a.m. URL], 54. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds)

The generally poor quality of health information on the world wide web (WWW) has caused preventable adverse outcomes. Quality management of information on the internet is therefore critical given its widespread use. In order to develop strategies for the safe use of drugs, we scored general and content quality of pages about sildenafil and performed an intervention to improve their quality.The internet was searched with Yahoo and AltaVista for pages about sildenafil and 303 pages were included. For assessment of content quality a score based on accuracy and completeness of essential drug information was assigned. For assessment of general quality, four criteria were evaluated and their association with high content quality was determined by multivariate logistic regression analysis. The pages were randomly allocated to either control or intervention group. Evaluation took place before, as well as 7 and 22 weeks after an intervention which consisted of two letters with individualized feedback information on the respective page which were sent electronically to the address mentioned on the page.Providing references to scientific publications or prescribing information was significantly associated with high content quality (odds ratio: 8.2, 95% CI 3.2, 20.5). The intervention had no influence on general or content quality.To prevent adverse outcomes caused by misinformation on the WWW individualized feedback to the address mentioned on the page was ineffective. It is currently probably the most straight-forward approach to inform lay persons about indicators of high information quality, i.e. the provision of references.

Introduction Pulmonary hypertension is a progressive disease of diverse origin with devastating consequences in adults as well as in children. The phosphodiesterase 5 inhibitor sildenafil successfully lowers pulmonary vascular resistance. However, because of its poor enteral absorption, resulting in ineffective plasma concentrations, responses in infants and children are often erratic. Case presentations We report the cases of two Caucasian boys, one born at term (case 1) and one aged 2.5 years (case 2), who had structural cardiac and pulmonary defects accompanied by symptomatic pulmonary hypertension. They received sildenafil enterally and sublingually and also intravenously in one of them. Plasma samples were taken at various time points to determine the plasma concentrations of sildenafil and its partially active metabolite. Sildenafil and N-desmethyl sildenafil were quantified using a validated liquid chromatography/mass spectrometry method. Oxygen partial pressure was determined from routine arterial blood gas samples. Conclusion In agreement with previous observations in adults, we found that sublingual sildenafil was more extensively absorbed in our two pediatric patients. After sublingual administration, sildenafil plasma concentrations increased by 314% to 361% compared to enteral dosing. Concurrently, the metabolic ratio increased, suggesting not only that the overall absorption was enhanced but also that first-pass metabolism was partially bypassed. In case 2, the free fraction of sildenafil was 0.9%, which is considerably less than in adults (4%), suggesting that, in case 2, higher plasma concentration would have been needed to achieve effects similar to those in adults. Sublingual sildenafil appears to be a promising alternative route of administration in children with poor enteral absorption.

To investigate the effect of acute P-glycoprotein inhibition by the multidrug-resistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the pharmacokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G).In a double-blind, three-way crossover study, the pharmacokinetic and potentially adverse pharmacodynamic effects (reaction time, transcutaneous PCO2, blood pressure) of morphine were compared with and without acute inhibition of P-glycoprotein by PSC. The effects of PSC alone were also evaluated. The study was performed in 18 healthy male volunteers and pharmacodynamic effects analysed by measuring the area under the effect (AUE) curve. 150 mg PSC (or its placebo) was given as an i.v. infusion over 2 h. With the expected inhibition of Pgp 1 h after starting PSC infusion, 7.5 morphine HCl (or its placebo) was infused over 2 h.The infusion of PSC resulted in blood concentrations expected to inhibit Pgp mediated transport. While the pharmacokinetics of plasma morphine and M6G. were unaffected there was a small but statistically significant increase in the AUC and Cmax of M3G (11.8 and 8.3%, respectively). The t(1/2) and tmax were unaffected. The pharmacokinetic parameters of PSC were not affected by coadministration with morphine. PSC did not significantly affect the adverse events of morphine, as assessed by spontaneous reporting. Compared with PSC alone, morphine elicited an increase in reaction time (Emax 48 ms, compared with the predose absolute reaction time of 644 ms), which was not detected by the alertness-drowsiness score, indicating only slight sedation. There was a significant decrease in systolic blood pressure (Emin -9 mm Hg), and a trend for a fall in diastolic blood pressure (Emin -14.5 mm Hg) and respiratory rate (Emin -1.8 breath x min(-1)). For all these parameters, the effects of PSC/morphine were similar to that of PSC alone, suggesting some attenuation of morphine's effect. In contrast, morphine caused a significant increase in PCO2 (Emax 0.69 kPa) compared to PSC alone, indicating slight respiratory depression. This increase was similar to that of the PSC/morphine combination.Acute inhibition of P-glycoprotein by PSC in this setting does not affect the pharmacokinetic or safety-related pharmacodynamic profile of morphine in a clinically significant manner.

Whereas cortical EEG effects of benzodiazepines are well characterized, information about benzodiazepine effects in other areas of the central nervous system is sparse. This study investigated the action of midazolam and its active metabolite alpha-hydroxy-midazolam on different parts of the auditory pathway in six healthy volunteers in a randomized, double-blind, three-way cross-over study.Acoustically evoked short (SLP) and middle (MLP) latency potentials, transitory evoked otoacoustic emissions (TEOAE), and EEG power spectra were analysed after short i. v. injections of placebo, or 0.15 mg kg-1 midazolam, or alpha-hydroxy-midazolam, respectively.All subjects fell asleep during the 4 min infusion of active drug. SLP showed a significant transient increase of Jewett wave V 10 min after injection for midazolam and alpha-hydroxy-midazolam while the latency of wave I was unchanged. Both benzodiazepines induced a marked and long-lasting MLP amplitude decrease for 240 min with slow recovery over the following 360 min. No changes of TEOAE were observed. In agreement with earlier reports, increases in EEG beta activity and decreases in alpha activity were observed after administration of either drug.Systemically administered benzodiazepines modulate the auditory pathway above the level of the cochlea. While SLP changes were closely associated with sedation and high plasma benzodiazepine concentrations, MLP effects persisted for hours after sedation even at low benzodiazepine plasma levels. Evoked potentials may therefore be more sensitive than EEG as a tool to monitor benzodiazepine effects.