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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.

Regulatory authorities put major emphasis on QT (interval)–prolonging properties of new molecular entities. Product information/Summaries of Product Characteristics (SmPCs) of multiple drugs contain warnings or contraindications regarding QT prolongation, e.g., on coadministration of QT‐prolonging drugs (QT drugs). To characterize the development of the QT drug burden, we performed a trend analysis of prescriptions and co‐prescriptions of QT drugs in a large geriatric inpatient cohort. The German SmPCs (status of 2014 and of 2021) and the year‐wise listings in the CredibleMeds® database from 2011 to 2021 were used as sources. There were 402,631 geriatric cases included. The group of QT drugs according to SmPCs in 2014, which must not be combined with other QT drugs, was less frequently involved in contraindicated co‐prescriptions in 2021 compared with 2015 (3.0% (2.5–3.7%) of cases with at least one of those drugs in 2021 vs. 4.0% (3.5–4.5%) in 2015), with citalopram, escitalopram, and amiodarone involved in nearly 90% of the co‐prescriptions. The number of CredibleMeds‐QT‐drugs per patient increased from 0.4 (SD=1.1) in 2011 to 1.8 (SD=3.9) in 2021. The percentage of contraindicated co‐prescriptions of drugs with known risk for torsade de pointes according to CredibleMeds® listings at the beginning of the respective years increased from 1.7% in 2011 to 6.1% in 2021. Considering the regularly updated CredibleMeds® QT drugs list, the contraindicated co‐prescriptions of QT drugs markedly increased in the last decade. If prescribers considered only the few most frequently (co‐) prescribed QT drugs, then most of the medication errors regarding QT drugs could be prevented.

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.

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.

Objective: Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency.Approach and Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling.Conclusions: Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.

Zusammenfassung Ziel der Studie Ziele der Studie waren einerseits die Erstellung einer Skala zur Erfassung zentral dämpfender bzw. aktivierender Wirkungen von Arzneimitteln sowie andererseits die Analyse der Fragestellung, ob dieser Summenwert bei Demenzerkrankten einen signifikanten Zusammenhang mit behandlungsbedürftigen Sturzereignissen aufweist. Explorativ wurde zusätzlich das Verschreibungsverhalten im Pflegeheim hinsichtlich PRISCUS-Liste, Anticholinergic Cognitive Burden List (ACB-Liste) und Psychopharmaka untersucht. Methodik Es wurden Daten einer randomisiert-kontrollierten Studie zur Untersuchung der Wirksamkeit der nicht-medikamentösen multimodalen Gruppentherapie MAKS® bei 139 Personen mit degenerativer Demenz in 5 Pflegeheimen evaluiert. Alle zum Zeitpunkt Studienbeginn verschriebenen Arzneimittel wurden hinsichtlich ihrer dämpfenden bzw. aktivierenden Wirkung auf einer 5-stufigen Skala von 2 klinisch-pharmakologischen Experten bewertet: Von stark aktivierend (Wert+2) bis stark dämpfend (Wert − 2). Die so ermittelten Werte aller verschriebenen Arzneimittel wurden für jede Person zu einem „Dämpfungsscore“ aufaddiert. Der Zusammenhang zwischen „Dämpfungsscore“ und Sturzereignissen mit Verletzungsfolge in einem Zeitraum von 12 Monaten wurde mithilfe der binär-logistischen Regressionsanalyse untersucht. Ergebnisse Knapp 30% aller Personen erhielten Arzneistoffe der PRISCUS-Liste, 50% bekamen einen Wirkstoff der ACB-Liste, 55% erhielten Psychopharmaka und 66% wurden mit mindestens fünf Arzneimitteln behandelt. 62% der Demenzerkrankten erhielten zentralnervös dämpfende Wirkstoffe. Im Beobachtungszeitraum kam es bei 36 der 139 Bewohnerinnen und Bewohner zu Sturzereignissen mit Verletzungsfolge. Der „Dämpfungsscore“ steht, multivariat analysiert, in signifikantem Zusammenhang (p=0,045) mit Sturzereignissen mit Verletzungsfolge. Eine stärkere zentralnervöse Dämpfung führte zu häufigeren Sturzereignissen. Schlussfolgerung Der „Dämpfungsscore“ ist ein geeignetes Maß, um das Ausmaß der zentralnervösen Dämpfung zu beschreiben. Aufgrund des signifikanten Einflusses der Dämpfung auf Sturzereignisse mit Verletzungsfolge sollte bei der Medikation von Demenzerkrankten stärker darauf geachtet werden, möglichst wenig zentral dämpfende Arzneimittel einzusetzen, um das Risiko für relevante unerwünschte Wirkungen zu reduzieren.

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 CredibleMedsDrugs listed on CredibleMedsOf the drugs currently listed on CredibleMedsA significant proportion of all drugs prescribed in the outpatient sector is associated with QT risks according to CredibleMeds

Background Circulating levels of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), are positively associated with the prevalence of metabolic syndrome (MetS) in cross-sectional investigations. It is unclear if circulating ADMA and other methylarginines are associated with incident MetS prospectively. Methods We related circulating ADMA, symmetric dimethylarginine (SDMA), L-arginine (ARG) concentrations (measured with a validated tandem mass spectrometry assay) and the ARG/ADMA ratio to MetS and its components in 2914 (cross-sectional analysis, logistic regression; mean age 58 years, 55% women) and 1656 (prospective analysis, Cox regression; mean age 56 years, 59% women) individuals from the Framingham Offspring Study who attended a routine examination. Results Adjusting for age, sex, smoking, and eGFR, we observed significant associations of ADMA (direct) and ARG/ADMA (inverse) with odds of MetS (N = 1461 prevalent cases; Odds Ratio [OR] per SD increment 1.13, 95%CI 1.04–1.22; and 0.89, 95%CI 0.82–0.97 for ADMA and ARG/ADMA, respectively). Upon further adjustment for waist circumference, systolic and diastolic blood pressure, glucose, high-density lipoprotein cholesterol, and triglycerides, we observed a positive relation between SDMA and MetS (OR per SD increment 1.15, 95% CI 1.01–1.30) but the other associations were rendered statistically non-significant. We did not observe statistically significant associations between any of the methylarginines and the risk of new-onset MetS (752 incident events) over a median follow-up of 11 years. Conclusion It is unclear whether dimethylarginines play an important role in the incidence of cardiometabolic risk in the community, notwithstanding cross-sectional associations. Further studies of larger samples are needed to replicate our findings.

PURPOSE Oral anticancer drugs (eg, kinase inhibitors) play an important role in cancer therapy. However, considerable challenges regarding medication safety of oral anticancer drugs have been reported. Randomized, controlled, multicenter studies on the impact of intensified clinical pharmacological/pharmaceutical care on patient safety and patient treatment perception are lacking. METHODS Patients were eligible for the randomized, multicenter AMBORA study, if they were newly started on any of the oral anticancer drugs approved in 2001 or later without restriction to certain tumor entities. Patients were randomly assigned to receive either standard of care (control group) or an additional, intensified clinical pharmacological/pharmaceutical care, which included medication management and structured patient counseling, over a period of 12 weeks (intervention group). Primary end points were the number of antitumor drug–related problems (ie, side effects and unresolved medication errors) and patient treatment satisfaction with the oral anticancer therapy after 12 weeks measured with the Treatment Satisfaction Questionnaire for Medication, category convenience. RESULTS Two hundred two patients were included. Antitumor drug–related problems were significantly lower in the intervention compared with the control group (3.85 v 5.81 [mean], P < .001). Patient treatment satisfaction was higher in the intervention group (Treatment Satisfaction Questionnaire for Medication, convenience; 91.6 v 74.4 [mean], P < .001). The hazard ratio for the combined end point of severe side effects (Common Terminology Criteria for Adverse Events ≥ 3), treatment discontinuation, unscheduled hospital admission, and death was 0.48 (95% CI, 0.32 to 0.71, P < .001) in favor of the intervention group. CONCLUSION Treatment with oral anticancer drugs is associated with a broad range of medication errors and side effects. An intensified clinical pharmacological/pharmaceutical care has considerable, positive effects on the number of medication errors, patient treatment perception, and severe side effects.

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, β-aminoisobutyric acid (β-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.

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.

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.This is a data analysis of a randomized controlled trial which tested the effects of a non-pharmacological multimodal activation therapy (MAKSNearly 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.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.Ziele der Studie waren einerseits die Erstellung einer Skala zur Erfassung zentral dämpfender bzw. aktivierender Wirkungen von Arzneimitteln sowie andererseits die Analyse der Fragestellung, ob dieser Summenwert bei Demenzerkrankten einen signifikanten Zusammenhang mit behandlungsbedürftigen Sturzereignissen aufweist. Explorativ wurde zusätzlich das Verschreibungsverhalten im Pflegeheim hinsichtlich PRISCUS-Liste, Anticholinergic Cognitive Burden List (ACB-Liste) und Psychopharmaka untersucht.Es wurden Daten einer randomisiert-kontrollierten Studie zur Untersuchung der Wirksamkeit der nicht-medikamentösen multimodalen Gruppentherapie MAKSKnapp 30% aller Personen erhielten Arzneistoffe der PRISCUS-Liste, 50% bekamen einen Wirkstoff der ACB-Liste, 55% erhielten Psychopharmaka und 66% wurden mit mindestens fünf Arzneimitteln behandelt. 62% der Demenzerkrankten erhielten zentralnervös dämpfende Wirkstoffe. Im Beobachtungszeitraum kam es bei 36 der 139 Bewohnerinnen und Bewohner zu Sturzereignissen mit Verletzungsfolge. Der „Dämpfungsscore“ steht, multivariat analysiert, in signifikantem Zusammenhang (p=0,045) mit Sturzereignissen mit Verletzungsfolge. Eine stärkere zentralnervöse Dämpfung führte zu häufigeren Sturzereignissen.Der „Dämpfungsscore“ ist ein geeignetes Maß, um das Ausmaß der zentralnervösen Dämpfung zu beschreiben. Aufgrund des signifikanten Einflusses der Dämpfung auf Sturzereignisse mit Verletzungsfolge sollte bei der Medikation von Demenzerkrankten stärker darauf geachtet werden, möglichst wenig zentral dämpfende Arzneimittel einzusetzen, um das Risiko für relevante unerwünschte Wirkungen zu reduzieren.

Background The metabolic syndrome is a cluster of cardiovascular risk factors and is highly predictive for development of cardiovascular diseases. An association between elevated plasma levels of the endogenous inhibitor of nitric oxide synthases asymmetric dimethylarginine (ADMA) and risk of cardiovascular diseases has been demonstrated in numerous epidemiological studies. ADMA can be catabolized by dimethylarginine dimethylaminohydrolase (DDAH) or metabolized through a much less understood alternative pathway by alanine:glyoxylate aminotransferase 2 (AGXT2) with the formation of α-keto-δ-(N,N-dimethylguanidino)valeric acid (ADGV). Previous RT-PCR and Western Blot studies suggested that Agxt2 is expressed in the mouse kidney and liver at comparable levels, while Northern Blot and in-situ RNA-hybridisation experiments demonstrated that the kidney is the main organ of Agxt2 expression in rats. Given this discrepancy, the goal of the current study was to analyse the expression of AGXT2 in human tissues. Material and methods We analyzed AGXT2 expression in human tissues from a normal tissue bank by RT-PCR and further validated the results by Western Blot. We also performed immunohistochemical staining for AGXT2 and double fluorescent staining with an anti-AGXT2 antibody and a monoclonal anti-mitochondrial antibody. Results We saw the strongest expression of AGXT2 in the kidney and liver and confirmed this results on protein level. By IHC staining we were able to show that AGXT2 is present in the convoluted tubule in the kidney and in the liver hepatocytes. The double fluorescent staining revealed mitochondrial localization of AGXT2. Conclusions Our current data suggest that both hepatocytes and kidney tubular epithelial cells are the major sources of AGXT2 in humans. We also demonstrated the mitochondrial localization of human AGXT2 enzyme.

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.

Seit dem 01.10.2016 haben gesetzlich Versicherte unter bestimmten Voraussetzungen einen Anspruch auf einen bundeseinheitlichen Medikationsplan (BMP, gemas § 31a SGB V, E‑Health Gesetz). Der Masnahmenkatalog des 3. Aktionsplans 2013–2015 zur Verbesserung der Arzneimitteltherapiesicherheit (AMTS) sah die Erprobung des BMP in der Praxis hinsichtlich seiner Akzeptanz und Praktikabilitat in drei Modellprojekten vor. Diese drei Projekte – MetropolMediplan 2016, Erfurt und PRIMA – werden vorgestellt und auf der Basis der gesammelten Erkenntnisse Empfehlungen abgeleitet. Der BMP wurde von den Teilnehmern in allen Projekten begrust und fuhrte zu einem Anstieg der Patientenzufriedenheit und Verbesserung der Medikationskompetenz. Sowohl die Arzte- als auch die Apothekerschaft bewerteten die interdisziplinare und multiprofessionelle Zusammenarbeit uber das Medium BMP sehr positiv. Negativ empfunden wurden der hohe zeitliche Aufwand zur Ersterstellung und Fortschreibung sowie die fehlende Telematikinfrastruktur zur Umsetzung einer elektronischen Version BMP. Ein Originaldatenabgleich der BMP-Daten mit den tatsachlich eingenommenen Medikamenten zeigte, dass lediglich bei 36 % der Falle der BMP und die tatsachlich eingenommenen Arzneistoffe ubereinstimmten. Obwohl die Erstellung einer Papierversion des BMP nicht die Problematik der Aktualitat und Vollstandigkeit der Medikation zum Behandlungszeitpunkt losen konnte, wurde ein signifikanter Effekt auf die AMTS durch den BMP belegt. Neben Vorschlagen zur Verbesserung der Prozessintegration des BMP in die Versorgungsroutine der Arzte- und Apothekerschaft wird eine elektronisch sektorenubergreifende Verfugbarkeit des BMP gefordert. Der BMP sollte zukunftig ein zentrales und wichtiges Instrument zur Verbesserung der AMTS darstellen.

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 N

Elevated plasma concentrations of the uremic toxin asymmetrical dimethylarginine (ADMA) and low plasma concentrations of L-homoarginine are independently associated with cardiovascular events and total mortality. Enzymes degrading ADMA [dimethylaminohydrolase 1 (DDAH1)] and synthesizing L-homoarginine [L-arginine:glycine amidinotransferase (AGAT)] are expressed in human proximal tubule cells. So far, it is not known which transport protein in the basolateral membrane of proximal tubule cells is mediating the uptake of ADMA into the cells for subsequent degradation or the export of intracellularly synthesized L-homoarginine. One study suggested that the uptake transporter OATP4C1 (gene symbol SLCO4C1) may be involved in the transport of ADMA and other uremic toxins. OATP4C1 is a member of the SLCO/SLC21 family of solute carriers, localized in the basolateral membrane of human proximal tubule cells. By using stably-transfected HEK cells overexpressing human OATP4C1, we demonstrate that ADMA and L-homoarginine are substrates of OATP4C1 with Km values of 232.1 μM and 49.9 μM, respectively. ADMA and the structurally related uremic toxin SDMA (100 μM) inhibited OATP4C1-mediated L-homoarginine uptake (P < 0.01), whereas other tested uremic toxins such as urea and p-cresyl sulfate have no effect on OATP4C1-mediated transport. Preloading experiments (300 μM for 60 min) with subsequent efflux studies revealed that OATP4C1 also facilitates efflux e.g. of L-homoarginine. Both ADMA and L-homoarginine are substrates of human OATP4C1. Because proximal tubule cells are one site of ADMA metabolism and L-homoarginine synthesis, we postulate a protective role of OATP4C1 by mediating uptake of ADMA from and export of L-homoarginine into the systemic circulation.

The use of cyclooxygenase (COX) inhibitors is increasingly common. Most of them are available for self-medication, either as analgesic or for cardio- and cerebrovascular prevention. We aimed to analyze adverse drug events (ADE) related to COX inhibitors and the concomitant use of proton pump inhibitors (PPI) according to guidelines in patients presenting at an emergency department (ED). In a prospective study, 2262 patients presenting consecutively at the ED of a tertiary care university teaching hospital were evaluated by intensive chart review in order to detect and classify all ADE. In this cross-sectional analysis all patients taking COX inhibitors at home were evaluated further. Of all evaluated patients, 753 (33.3 %) took COX inhibitors at home, 258 (34.3 %) with concomitant PPI. A total of 168 (22.3 %) patients suffered from at least one ADE related to COX inhibitors. The most common ADE observed were anemia (55.9 %) and gastrointestinal ADE (31.6 %, e. g., bleeding, gastritis, and ulcer). In 10.1 % of patients, a medication error (e. g., intake without proper clinical indication) contributed to the ADE and in 40.8 % of the ADE involved further contributing drugs. Only 38.8–42.1 % of patients with a high gastrointestinal risk were prescribed a PPI concomitantly. ADE related to COX inhibitors were found in every fifth patient taking COX inhibitors. One-tenth of all ADE involving COX inhibitors were related to medication errors. The guideline-based concomitant use of PPI was only in part implemented.

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.

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 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.

Background— Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l -arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers. Methods and Results— This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci ( DDAH1, MED23, Arg1 , and AGXT2 ) associated with the interindividual variability in ADMA, l -arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Conclusions— These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l -arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.