A supervised machine-learning approach for the efficient development of a multi method (LC-MS) for a large number of drugs and subsets thereof: focus on oral antitumor agents.

OBJECTIVES: Accumulating evidence argues for a more widespread use of therapeutic drug monitoring (TDM) to support individualized medicine, especially for therapies where toxicity and efficacy are critical issues, such as in oncology. However, development of TDM assays struggles to keep pace with the rapid introduction of new drugs. Therefore, novel approaches for faster assay development are needed that also allow effortless inclusion of newly approved drugs as well as customization to smaller subsets if scientific or clinical situations require. METHODS: We applied and evaluated two machine-learning approaches i.e., a regression-based approach and an artificial neural network (ANN) to retention time (RT) prediction for efficient development of a liquid chromatography mass spectrometry (LC-MS) method quantifying 73 oral antitumor drugs (OADs) and five active metabolites. Individual steps included training, evaluation, comparison, and application of the superior approach to RT prediction, followed by stipulation of the optimal gradient. RESULTS: Both approaches showed excellent results for RT prediction (mean difference ± standard deviation: 2.08 % ± 9.44 % ANN; 1.78 % ± 1.93 % regression-based approach). Using the regression-based approach, the optimum gradient (4.91 % MeOH/min) was predicted with a total run time of 17.92 min. The associated method was fully validated following FDA and EMA guidelines. Exemplary modification and application of the regression-based approach to a subset of 14 uro-oncological agents resulted in a considerably shortened run time of 9.29 min. CONCLUSIONS: Using a regression-based approach, a multi drug LC-MS assay for RT prediction was efficiently developed, which can be easily expanded to newly approved OADs and customized to smaller subsets if required.

[INTERPOLAR-prospective, interventional studies as part of the Medical Informatics Initiative to improve medication therapy safety in healthcare]. / INTERPOLAR ­ prospektive, interventionelle Studien im Rahmen der Medizininformatik-Initiative zur Verbesserung der Arzneimitteltherapiesicherheit in der Krankenversorgung.

Medication analyses by ward pharmacists are an important measure of drug therapy safety (DTS). Medication-related problems (MRPs) are identified and resolved with the attending clinicians. However, staff resources for extended medication analyses and complete documentation are often limited. Until now, data required for the identification of risk patients and for an extended medication analysis often had to be collected from various parts of the institution's internal electronic medical record (EMR). This error-prone and time-consuming process is to be improved in the INTERPOLAR (INTERventional POLypharmacy-Drug interActions-Risks) project using an IT tool provided by the data integration centers (DIC).INTERPOLAR is a use case of the Medical Informatics Initiative (MII) that focuses on the topic of DTS. The planning phase took place in 2023, with routine implementation planned from 2024. DTS-relevant data from the EMR is to be presented and the documentation of MRPs in routine care is to be facilitated. The prospective multicenter, cluster-randomized INTERPOLAR­1 study serves to evaluate the benefits of IT support in routine care. The aim is to show that more MRPs can be detected and resolved with the help of IT support. For this purpose, six normal wards will be selected at each of eight university hospitals, so that 48 clusters (with a total of at least 70,000 cases) are available for randomization.

Inconsistencies of absolute drug-drug contraindication reports: Analysis of Summaries of Product Characteristics of commonly prescribed drugs.

AIMS: Prescribing information should follow a defined structure to help prescribers easily find required information. Often information appears in different sections of Summaries of Product Characteristics (SmPCs) in an inconsistent way. Still unknown is how this inconsistency affects absolute contraindications and how it can be improved. Thisstudy aimed to evaluate the structure of absolute contraindications in SmPCs based on absolute drug-drug contraindications (DDCI) in the section 'contraindications' and references to sections 'special warnings and precautions for use' (here as 'warnings') and 'interaction with other medicinal products and other forms of interaction' (here as 'interactions'). METHODS: SmPCs of 693 commonly prescribed drugs were analysed regarding absolute DDCI in 'contraindications' sections. References to sections on 'warnings' and 'interactions' were evaluated to characterize information provided about DDCI. RESULTS: Of 693 analysed SmPCs, 138 (19.9%) contained ≥1 absolute DDCI. Of 178 SmPCs that referred to sections on 'warnings' or 'interactions', 131 (73.6%) did not contain further information on absolute DDCI, whereas 47 (26.4%) did. Such additional information was found in sections on 'interactions' and 'warnings' in 41 (87.2%) and 9 (19.1%) SmPCs, respectively. CONCLUSIONS: Information regarding absolute DDCI was found not only in sections on 'contraindications' but also in sections on 'warnings' and 'interactions'. Information was not given with consistently straightforward phrasing and structure and so can leave uncertainty for prescribers. To improve drug safety, clear definitions and wording for absolute and relative contraindications should be provided, ideally in tables.

Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers.

BACKGROUND: In patients with type 2 diabetes (T2D) sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve glycaemic control as well as cardiovascular and renal outcomes. Their effects on L-arginine (Arg) related risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA) and the protective biomarker L-homoarginine (hArg) linking T2D to cardiovascular and renal disease have not yet been reported. METHODS: Plasma and 24-h urine samples taken before and after 6 weeks of treatment were available from two prospective, randomized, double-blind, placebo-controlled, cross-over trials with empagliflozin (71 patients analyzed, NCT02471963) and dapagliflozin (59 patients analyzed, NCT02383238). In these samples, concentrations of hArg, Arg, ADMA, SDMA, and creatinine were determined by liquid-chromatography coupled to tandem mass-spectrometry. Additionally, intraindividual changes of the biomarkers in plasma were correlated with intraindividual changes of clinical parameters. RESULTS: Treatment with empagliflozin and dapagliflozin was associated with a reduction of plasma hArg by 17.5% and 13.7% (both p < 0.001), respectively, and increase in plasma SDMA concentration of 6.7% and 3.6%, respectively (p < 0.001 and p < 0.05), while plasma Arg and ADMA concentrations were not significantly altered. 24-h urinary excretion of ADMA was reduced by 15.2% after treatment with empagliflozin (p < 0.001) but not after dapagliflozin treatment, while excretion of the other markers was not significantly altered. Renal clearance of SDMA was reduced by 9.1% and 3.9% for both drugs (both p < 0.05). A reduction in ADMA clearance was observable after empagliflozin treatment only (- 15.5%, p < 0.001), but not after dapagliflozin. Renal clearance of hArg and Arg was not significantly altered. Treatment effects on L-arginine related biomarkers were not constantly correlated with effects on glycated hemoglobin, fasting plasma glucose, body mass index, and systolic blood pressure. CONCLUSIONS: Treatment with SGLT-2 inhibitors has divergent effects on Arg-related biomarkers and could affect risk estimates associated with these markers. The observed effects are unlikely to explain the known cardiovascular and renal benefits of treatment with empagliflozin or dapagliflozin but still may indicate new therapeutic approaches in patients treated with SGLT-2 inhibitors. Trial registration http://www.clinicaltrials.gov : NCT02471963 (registered 15th June 2015, retrospectively registered) and NCT02383238.

Screening of commonly prescribed drugs for effects on the CAT1-mediated transport of L-arginine and arginine derivatives.

The cationic amino acid transporter 1 (CAT1/SLC7A1) plays a key role in the cellular uptake or export of L-arginine and some of its derivatives. This study investigated the effect of 113 chemically diverse and commonly used drugs (at 20 and 200 µM) on the CAT1-mediated cellular uptake of L-arginine, L-homoarginine, and asymmetric dimethylarginine (ADMA). Twenty-three (20%) of the tested substances showed weak inhibitory or stimulatory effects, but only verapamil showed consistent inhibitory effects on CAT1-mediated transport of all tested substrates.

The CredibleMeds® list: Usage of QT interval prolonging drugs in Germany and discordances with prescribing information.

AIMS: A substantial number of Summaries of Product Characteristics (SmPCs)/Prescribing Information (PI) have warnings or contraindications on QT interval prolongation. The goal of this work was to quantify usage of QT interval prolonging drugs according to the CredibleMeds® database of the German outpatient drug prescription market and to evaluate discrepancies between German SmPCs/US PI and CredibleMeds® . METHODS: Drugs listed on CredibleMeds® with known, possible or conditional risk for torsade de pointes were evaluated from 2000 to 2020. The German drug prescription report was used as source for defined daily dose- (DDD-) based prescriptions of the German outpatient drug prescription market of the public health insurance system. German SmPCs and US PI of 253 CredibleMeds® -listed drugs were evaluated for contents regarding QT interval prolongation. RESULTS: Of the drugs currently listed on CredibleMeds® , 59.7% (95% confidence interval [CI] 53.5-65.5%) were listed after 2012. Due to newly listed drugs, the proportion of DDDs of CredibleMeds® drugs among all prescriptions increased from 4.6% in 2013 to 21.1% in 2019. DDD-based usage of the CredibleMeds® drugs already listed in 2013 was similar in 2019. Among the drugs with known QT risk according to CredibleMeds® , 7.5% (95% CI 2.6-19.9%) of German SmPCs and 21.1% (95% CI 11.1-36.3%) of US PI had no mention of QT issues whatsoever. CONCLUSION: A significant proportion of all drugs prescribed in the outpatient sector is associated with QT risks according to CredibleMeds® . SmPCs and PI should systematically be evaluated for concordance with the widely used CredibleMeds® database to increase medication safety.

Use of medication data alone to identify diagnoses and related contraindications: Application of algorithms to close a common documentation gap.

AIMS: Automated checks for medication-related problems have become a cornerstone of medication safety. In many clinical settings medication checks remain confined to drug-drug interactions because only medication data are available in an adequately coded form, leaving possible contraindicated drug-disease combinations unaccounted for. Therefore, we devised algorithms that identify frequently contraindicated diagnoses based on medication patterns related to these diagnoses. METHODS: We identified drugs that are associated with diseases constituting common contraindications based on their exclusive use for these conditions (such as allopurinol for gout or salbutamol for bronchial obstruction). Expert-based and machine learning algorithms were developed to identify diagnoses based on highly specific medication patterns. The applicability, sensitivity and specificity of the approach were assessed by using an anonymized real-life sample of medication and diagnosis data excerpts from 3506 discharge records of geriatric patients. RESULTS: Depending on the algorithm, the desired focus (i.e., sensitivity vs. specificity) and the disease, we were able to identify the diagnoses gout, epilepsy, coronary artery disease, congestive heart failure and bronchial obstruction with a specificity of 44.0-99.8% (95% CI 41.7-100.0%) and a sensitivity of 3.8-83.1% (95% CI 1.0-86.1%). Using only medication data, we were able to identify 123 (51.3%) of 240 contraindications identified by experts with access to medication data and diagnoses. CONCLUSION: This study provides a proof of principle that some key diagnosis-related contraindications can be identified based on a patient's medication data alone, while others cannot be identified. This approach offers new opportunities to analyse drug-disease contraindications in community pharmacy or clinical routine data.

Vectorial transport of the arginine derivatives asymmetric dimethylarginine (ADMA) and L-homoarginine by OATP4C1 and P-glycoprotein studied in double-transfected MDCK cells.

Elevated plasma concentrations of the uremic toxin asymmetric dimethylarginine (ADMA) and low plasma concentrations of L-homoarginine are independently associated with cardiovascular events and mortality. Key enzymes involved in the homeostasis of both arginine derivatives are expressed in proximal tubule cells of the kidney. To get access to these enzymes, transport proteins are important. One of the transporters mediating the transport of ADMA and L-homoarginine is the solute carrier superfamily (SLC) member OATP4C1, located in the basolateral membrane of proximal tubule cells. To gain insights into the role of export pumps in the transport of both substances, we established a double-transfected MDCK cell line expressing OATP4C1 and the export pump P-glycoprotein (P-gp). Using MDCK cell monolayers, we demonstrated in time-dependent and concentration-dependent vectorial transport experiments that ADMA and L-homoarginine are transported from the basolateral to the apical compartment of MDCK-OATP4C1-P-gp cells with significantly higher transport rates compared to single-transfected MDCK-OATP4C1, MDCK-P-gp and MDCK-VC (control) cells (e.g. transport ratio MDCK-OATP4C1-P-gp/MDCK-VC: for 50 µM ADMA = 2.0-fold, for 50 µM L-homoarginine = 3.4-fold). These results indicate that both OATP4C1 and P-gp transport the arginine derivatives ADMA and L-homoarginine and are, therefore, important for the homoeostasis of both substances.

Drugs linked to plasma homoarginine in chronic kidney disease patients-a cross-sectional analysis of the German Chronic Kidney Disease cohort.

BACKGROUND: Elevated plasma concentrations of symmetric and asymmetric dimethylarginine (SDMA and ADMA, respectively) and a lower plasma concentration of the structurally related homoarginine are commonly observed in patients with chronic kidney disease (CKD) and independently predict total mortality as well as progression of renal disease. We aimed to identify drugs that may alter this adverse metabolite pattern in a favourable fashion. METHODS: Plasma ADMA, SDMA, homoarginine and l-arginine were determined by liquid chromatography-tandem mass spectrometry in 4756 CKD patients ages 18-74 years with an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or an eGFR >60 mL/min/1.73 m2 and overt proteinuria who were enrolled in the German Chronic Kidney Disease (GCKD) study. Associations between laboratory, clinical and medication data were assessed. RESULTS: Intake of several commonly used drugs was independently associated with plasma concentrations of homoarginine and/or related metabolites. Among these, the peroxisome proliferator-activated receptor alpha (PPAR-α) agonist fenofibrate was associated with the most profound differences in ADMA, SDMA and homoarginine plasma concentrations: 66 patients taking fenofibrate had a multivariable adjusted odds ratio (OR) of 5.83 [95% confidence interval (CI) 2.82-12.03, P < 0.001] to have a plasma homoarginine concentration above the median. The median homoarginine plasma concentration in patients taking fenofibrate was 2.30 µmol/L versus 1.55 in patients not taking the drug (P < 0.001). In addition, fibrates were significantly associated with lower plasma SDMA and higher l-arginine concentrations. In contrast, glucocorticoids were associated with lower plasma homoarginine, with adjusted ORs of 0.52 (95% CI 0.40-0.67, P < 0.001) and 0.53 (95% CI 0.31-0.90, P = 0.018) for prednisolone and methylprednisolone, respectively. CONCLUSIONS: In a large cohort of CKD patients, intake of fenofibrate and glucocorticoids were independently associated with higher and lower plasma homoarginine concentrations, respectively. Effects on plasma homoarginine and methylarginines warrant further investigation as potential mechanisms mediating beneficial or adverse drug effects.

Trimethylamine-N-oxide (TMAO) determined by LC-MS/MS: distribution and correlates in the population-based PopGen cohort.

Background Accumulating evidence indicates that trimethylamine-N-oxide (TMAO) may play a causal role in cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes (T2D). TMAO plasma concentrations show considerable intra- and inter-individual variation, underscoring the need for a reference interval in the general population to identify elevated TMAO concentrations. Methods TMAO concentrations were determined using an LC-MS/MS assay in a community-based sample of the PopGen control cohort consisting of 694 participants (54% men; aged 25-82 years) free of clinical CVD, CKD and T2D. We defined reference intervals for TMAO concentrations in human plasma using the 2.5th and 97.5th percentiles. Using multivariable regression analysis we analyzed the association of estimated glomerular filtration rate (eGFR), sex, and dietary intake and TMAO plasma concentrations. Results TMAO plasma concentrations were positively skewed and differed by sex. The median TMAO plasma concentration in men was 3.91 (Q1-Q3: 2.87-6.10) µmol/L and the reference interval 1.28-19.67 µmol/L (2.5th-97.5th percentile). In women median TMAO plasma concentration was 3.56 (Q1-Q3: 2.41-5.15) µmol/L and the reference interval 1.08-17.12 µmol/L. In multivariable regression analysis plasma TMAO was associated with sex, renal function and diet. The association of TMAO and diet was significant for intake of fish and shellfish in men only. Conclusions In a community-based sample free of apparent CVD and renal disease, we report the distribution of TMAO plasma concentrations with sex, renal function and diet as factors associated with plasma TMAO, and suggest reference intervals. These data may facilitate standardized comparisons of TMAO across populations.

[Impact of Sedating Drugs on Falls Resulting Injuries Among People with Dementia in a Nursing Home Setting]. / Einfluss zentralnervös dämpfender Arzneimittel auf Stürze mit Verletzungsfolgen bei Menschen mit Demenz in Pflegeheimen.

AIM: The aims of this study were to create a scale for measuring the sedating and activating effects of drugs and to analyse if the total value of this scale correlates significantly with falls requiring medical treatment in dementia patients. Furthermore, prescription of drugs in nursing homes included in the PRISCUS-List, Anticholinergic Cognitive Burden List (ACB-List) and usage of psychotropic drugs were investigated. METHOD: This is a data analysis of a randomized controlled trial which tested the effects of a non-pharmacological multimodal activation therapy (MAKS®) in 139 patients with degenerative dementia in 5 nursing homes. At the beginning of the study, all prescribed drugs were rated on a five-tier scale by 2 pharmacologists based on the drugs' sedating or activating effects. The scale ranged from severely activating (+2) to severely sedating (- 2). The "central nervous system (CNS) depressant score" of each patient was calculated by summing up the scale value of all the medications they were taking. The correlation between CNS-depressant score and falls resulting in injuries within an observation period of 12 months was investigated by binary logistic regression analysis. RESULTS: Nearly 30% of the nursing home residents received drugs listed in the PRISCUS-list, 50% received drugs on the ACB-List, 55% took psychotropic drugs and 66% received at least 5 drugs. Sedating drugs were prescribed to 62% of patients. During the observation period, 36 out of 139 nursing home residents suffered falls and medical treatment was necessary. In multivariate analysis, the CNS-depressant score was associated significantly (p=0.045) with falls with resulting injuries. Increased sedation resulted in a higher number of fall incidents. CONCLUSIONS: The CNS-depressant score is a useful tool to describe the degree of sedation. Due to the significant association between sedation and falls resulting in injuries, the sedating medication of people suffering from dementia should be minimised as much as possible to reduce the risk of undesirable side effects.

Establishment of reference values for the lysine acetylation marker Nɛ-acetyllysine in small volume human plasma samples by a multi-target LC-MS/MS method.

Cardiovascular disease (CVD) and chronic kidney disease (CKD) constitute substantial burdens for public health. The identification and validation of risk markers for CVD and CKD in epidemiological studies requires frequent adaption of existing analytical methods as well as development of new methods. In this study, an analytical procedure to simultaneously quantify ten endogenous biomarkers for CVD and CKD is described. An easy-to-handle sample preparation requiring only 20 µL of human plasma is followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The method was successfully validated according to established guidelines meeting required criteria for accuracy, precision, recovery, linearity, selectivity, and limits of quantification. The scalability of the method for application in larger cohorts was assessed using a set of plasma samples from healthy volunteers (n = 391) providing first reference values for the recently established biomarker Nɛ-acetyllysine (Nɛ-AcLys). Other biomarkers analyzed were creatinine, ß-aminoisobutyric acid (ß-AIB), carnitine, 1-methylnicotinamide (1-MNA), citrulline, symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA), homoarginine (hArg), and ornithine. All obtained results are within reference values specified elsewhere. Overall, these results demonstrate the suitability of the method for simultaneous quantification of ten endogenous biomarkers for CVD and CKD in plasma samples from larger cohorts and allow validation of Nɛ-AcLys as a biomarker in large cohorts.

[Standardized national medication plan : The pilot projects MetropolMediplan 2016, model region Erfurt, and PRIMA]. / Der bundeseinheitliche Medikationsplan in der Praxis : Die Pilotprojekte MetropolMediplan 2016, Modellregion Erfurt und PRIMA.

Since 1 October 2016, all legally insured persons are entitled to a nationwide medication plan (BMP) under certain conditions (according to § 31a SGB V, E-Health Law). The catalogue of measures of the 3rd Action Plan 2013-2015 for the improvement of drug therapy safety (AMTS) provided for the testing of a medication plan in practice, including its acceptance and practicability in three model projects. These three projects - MetropolMediplan 2016, Erfurt, and PRIMA - are presented and recommendations are derived on the basis of the collected findings. Overall, the BMP was welcomed by the participating patients in all projects and led to an increase in satisfaction and an improvement in competence with regard to medication. Both doctors and pharmacists rated the interdisciplinary cooperation via the medium BMP very positively. The high effort and lack of technical infrastructure without electronic availability of the last current version of a BMP of the individual patient was perceived as negative. An original data comparison of the BMP data with the drugs actually taken in the MetropolMediplan 2016 project showed that only 36% of the patients were in agreement with the BMP and the drugs presently taken. The paper version of the BMP has therefore not yet been able to solve the problem of the timeliness and completeness of the medication. In addition to various proposals for the further development of BMP, all parties involved require the BMP to be available electronically across all sectors. The BMP should therefore be an important instrument for improving AMTS in the future.

Asymmetric dimethylarginine, related arginine derivatives, and incident atrial fibrillation.

BACKGROUND: Oxidative stress plays an important role in the development of atrial fibrillation (AF). Arginine derivatives including asymmetric dimethylarginine (ADMA) are central to nitric oxide metabolism and nitrosative stress. Whether blood concentrations of arginine derivatives are related to incidence of AF is uncertain. METHODS AND RESULTS: In 3,310 individuals (mean age 58 ± 10 years, 54% women) from the community-based Framingham Study, we prospectively examined the relations of circulating levels of ADMA, l-arginine, symmetric dimethylarginine (SDMA), and the ratio of l-arginine/ADMA to incidence of AF using proportional hazards regression models. Over a median follow-up time of 10 years, 247 AF cases occurred. Using age- and sex-adjusted regression models, ADMA was associated with a hazard ratio of 1.15 per 1-SD increase in loge-biomarker concentration (95% CI 1.02-1.29, P = .02) for AF, which was no longer significant after further risk factor adjustment (hazard ratio 1.09, 95% CI 0.97-1.23, P = .15). Neither l-arginine nor SDMA was related to new-onset AF. A clinical model comprising clinical risk factors for AF (for age, sex, height, weight, systolic blood pressure, diastolic blood pressure, current smoking, diabetes, hypertension treatment, myocardial infarction, and heart failure; c statistic = 0.781; 95% CI 0.753-0.808) was not improved by the addition of ADMA (0.782; 95% CI 0.755-0.809). CONCLUSIONS: Asymmetric dimethylarginine and related arginine derivatives were not associated with incident AF in the community after accounting for other clinical risk factors and confounders. Its role in the pathogenesis of AF needs further refinement.

Potentially inappropriate medication in the elderly in Germany: an economic appraisal of the PRISCUS list.

BACKGROUND: Several lists of potentially inappropriate medication (PIM) for elderly patients have been developed worldwide in recent years. Those lists intend to reduce prescriptions of drugs that carry an unnecessarily high risk of adverse drug events in elderly patients. In 2010, an expert panel published the PRISCUS list for the German drug market. This study calculates the amount of drug reimbursement for PIM in Germany and potential cost effects from the perspective of statutory health insurance when these are replaced by the substitutes recommended by the PRISCUS list. METHODS: Register-based data for the 30 top-selling drugs on the PRISCUS list in 2009 for patients greater than or equal to 65 years of age were provided by the Scientific Institute of the German Local Health Care Fund. We calculated the percentage of sales and defined daily doses for patients greater than or equal to 65 years of age compared with the total statutory health insurance population. Reimbursement costs for the recommended substitutions were estimated by considering different scenarios. RESULTS: In 2009, drug reimbursement for the 30 top-selling PIM prescribed to patients greater than or equal to 65 years of age were calculated to be €305.7 million. Prescribing the recommended substitution medication instead of PIM would lead to an increased total reimbursement cost for the German health care system ranging between from €325.9 million to €810.0 million. CONCLUSIONS: The results show that the substitution of PIM by medication deemed to be more appropriate for the elderly comes along with additional costs. Consequently, there is no short-term incentive for doing so from a payer perspective. Future studies have to consider the long-term effects and other sectors.

Dental procedures in patients treated with antiplatelet or oral anticoagulation therapy - an anonymous survey.

OBJECTIVE: To investigate how German dentists adhere to recommendations regarding dental treatment of patients taking antiplatelet or oral anticoagulation therapy for cardiovascular protection. BACKGROUND: Discontinuation of antiplatelet or oral anticoagulation therapy prior to dental procedures is usually not recommended because the risk of thromboembolic events is higher than that of significant procedure-related bleeding. MATERIALS AND METHODS: An anonymous questionnaire regarding the handling of and experiences with patients taking aspirin (acetylsalicylic acid) or vitamin-K-antagonists (phenprocoumon) was distributed to approximately 4500 dentists attending the national German Dentists Day 2011. RESULTS: Of 146 dentists who completed the questionnaire 77.4% and 27.6% stated that they perform tooth extractions under continued therapy with aspirin or vitamin-K-antagonists, respectively. When asked regarding the INR or Quick values, they require for tooth extractions in patients taking oral anticoagulants 29.5% of the dentists provided values that were outside the safe range (INR ≤1.5 or ≥3.5) and 90.7% accepted values too old to be clinically reliable. For pain relief after dental procedures, 71.2% of the dentists recommended ibuprofen notwithstanding the fact that it attenuates protective effects of aspirin and 10.2% would discontinue aspirin and prescribe ibuprofen or paracetamol (acetaminophen). CONCLUSION: Despite similar recommendations the majority of dentists perform tooth extractions in patients taking aspirin but not in patients taking vitamin-K-antagonists. Moreover, a potentially unfavourable drug interaction of aspirin and ibuprofen is frequently not considered. In patients taking vitamin-K-antagonists too many dentists rely on laboratory values that are too old or outside the recommended range.

N(1)-methylnicotinamide as an endogenous probe for drug interactions by renal cation transporters: studies on the metformin-trimethoprim interaction.

PURPOSE: N(1)-methylnicotinamide (NMN) was proposed as an in vivo probe for drug interactions involving renal cation transporters, which, for example, transport the oral antidiabetic drug metformin, based on a study with the inhibitor pyrimethamine. The role of NMN for predicting other interactions with involvement of renal cation transporters (organic cation transporter 2, OCT2; multidrug and toxin extrusion proteins 1 and 2-K, MATE1 and MATE2-K) is unclear. METHODS: We determined inhibition of metformin or NMN transport by trimethoprim using cell lines expressing OCT2, MATE1, or MATE2-K. Moreover, a randomized, open-label, two-phase crossover study was performed in 12 healthy volunteers. In each phase, 850 mg metformin hydrochloride was administered p.o. in the evening of day 4 and in the morning of day 5. In phase B, 200 mg trimethoprim was administered additionally p.o. twice daily for 5 days. Metformin pharmacokinetics and effects (measured by OGTT) and NMN pharmacokinetics were determined. RESULTS: Trimethoprim inhibited metformin transport with K i values of 27.2, 6.3, and 28.9 µM and NMN transport with IC50 values of 133.9, 29.1, and 0.61 µM for OCT2, MATE1, and MATE2-K, respectively. In the clinical study, trimethoprim increased metformin area under the plasma concentration-time curve (AUC) by 29.5 % and decreased metformin and NMN renal clearances by 26.4 and 19.9 %, respectively (p ≤ 0.01). Moreover, decreases of NMN and metformin renal clearances due to trimethoprim correlated significantly (r S=0.727, p=0.010). CONCLUSIONS: These data on the metformin-trimethoprim interaction support the potential utility of N(1)-methylnicotinamide as an endogenous probe for renal drug-drug interactions with involvement of renal cation transporters.

Adverse drug events in patients admitted to an emergency department: an analysis of direct costs.

PURPOSE: Several economic evaluations of adverse drug events (ADEs) exist, but the underlying methodology has not been standardized so far. The aim of the study was to combine prospective, intensive pharmacovigilance methods, and standardized accounting data to calculate direct costs of community-acquired ADEs (caADEs) contributing to emergency department (ED) admission and subsequent hospitalization. METHODS: A prospective observational study with three phases extending over 2 years was implemented in a 749 bed tertiary care hospital with an annual ED census of approximately 45 000 patients. The patient records of all adult non-trauma ED admissions were systematically analyzed by a team of emergency physicians, clinical pharmacologists, and pharmacists for potential ADE. Associated diagnosis related group costs were extracted from standardized accounting data. RESULTS: Of 2262 patients attending the ED during the study periods, the hospitalization of 366 patients (16.2%) was related to one or more caADEs of which 97.5% were considered predictable and 62.0% were classified as preventable. The mean caADE-related diagnosis related group costs were €2743 (95% bias-corrected and accelerated CI: €2498 to €3018). Extrapolated to a national scale, this corresponds to caADE-related costs of €2.245bn for the German health insurance funds, annually. Costs of €1.310bn could be attributed to events classified as predictable and preventable. CONCLUSIONS: In an ED, caADEs are frequent, and a significant proportion of these events and their related costs appear to be predictable and preventable. The ED as a first-line provider for ADE cases appears to be an appropriate environment to implement strategic and operative improvements for enhanced patient safety.

Role of alanine:glyoxylate aminotransferase 2 in metabolism of asymmetric dimethylarginine in the settings of asymmetric dimethylarginine overload and bilateral nephrectomy.

BACKGROUND: Asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict complications and mortality in cardiovascular and renal diseases. Alanine:glyoxylate aminotransferase 2 (AGXT2) can metabolize both ADMA and SDMA; however, this metabolic pathway is still poorly understood. The goal of our study was to test the hypothesis that AGXT2 is compensatory upregulated in the settings of ADMA overload and bilateral nephrectomy. METHODS: ADMA was infused for 3 days using osmotic minipumps in mice. Half of the mice underwent bilateral nephrectomy 24 h before the end of the infusion. RESULTS: Infusion of ADMA caused a 3- to 4-fold increase in plasma and urine ADMA levels and a 2- to 3-fold increase in plasma and urine levels of the ADMA-specific metabolite of AGXT2 α-keto-δ-(N,N-dimethylguanidino)valeric acid (DMGV). Bilateral nephrectomy led to an ∼4-fold increase of plasma SDMA levels, but did not change plasma ADMA levels. Interestingly, plasma levels of DMGV were elevated 32-fold in the mice, which underwent bilateral nephrectomy. Neither bilateral nephrectomy nor ADMA infusion caused upregulation of AGXT2 expression or activity. CONCLUSIONS: Our data demonstrate that short-term elevation of systemic levels of ADMA leads to a dramatic increase of DMGV formation without upregulation of AGXT2 expression or activity, which suggests that AGXT2-mediated pathway of ADMA metabolism is not saturated under normal conditions and may play a major role in the maintenance of ADMA homeostasis in the setting of local or systemic elevation of ADMA levels.

Application of the Pareto principle to identify and address drug-therapy safety issues.

PURPOSE: Adverse drug events (ADE) and medication errors (ME) are common causes of morbidity in patients presenting at emergency departments (ED). Recognition of ADE as being drug related and prevention of ME are key to enhancing pharmacotherapy safety in ED. We assessed the applicability of the Pareto principle (~80 % of effects result from 20 % of causes) to address locally relevant problems of drug therapy. METHODS: In 752 cases consecutively admitted to the nontraumatic ED of a major regional hospital, ADE, ME, contributing drugs, preventability, and detection rates of ADE by ED staff were investigated. Symptoms, errors, and drugs were sorted by frequency in order to apply the Pareto principle. RESULTS: In total, 242 ADE were observed, and 148 (61.2 %) were assessed as preventable. ADE contributed to 110 inpatient hospitalizations. The ten most frequent symptoms were causally involved in 88 (80.0 %) inpatient hospitalizations. Only 45 (18.6 %) ADE were recognized as drug-related problems until discharge from the ED. A limited set of 33 drugs accounted for 184 (76.0 %) ADE; ME contributed to 57 ADE. Frequency-based listing of ADE, ME, and drugs involved allowed identification of the most relevant problems and development of easily to implement safety measures, such as wall and pocket charts. CONCLUSIONS: The Pareto principle provides a method for identifying the locally most relevant ADE, ME, and involved drugs. This permits subsequent development of interventions to increase patient safety in the ED admission process that best suit local needs.