Pharmacogenetics of oral antidiabetic drugs

Oral antidiabetic drugs (OADs) are used for more than a half-century in the treatment of type 2 diabetes. Only in the last five years, intensive research has been conducted in the pharmacogenetics of these drugs based mainly on the retrospective register studies, but only a handful of associations detected in these studies were replicated. The gene variants in CYP2C9, ABCC8/KCNJ11, and TCF7L2 were associated with the effect of sulfonylureas. CYP2C9 encodes sulfonylurea metabolizing cytochrome P450 isoenzyme 2C9, ABCC8 and KCNJ11 genes encode proteins constituting ATP-sensitive K+ channel which is a therapeutic target for sulfonylureas, and TCF7L2 is a gene with the strongest association with type 2 diabetes. SLC22A1, SLC47A1, and ATM gene variants were repeatedly associated with the response to metformin. SLC22A1 and SLC47A1 encode metformin transporters OCT1 and MATE1, respectively. The function of a gene variant near ATM gene identified by a genome-wide association study is not elucidated so far. The first variant associated with the response to gliptins is a polymorphism in the proximity of CTRB1/2 gene which encodes chymotrypsinogen. Establishment of diabetes pharmacogenetics consortia and reduction in costs of genomics might lead to some significant clinical breakthroughs in this field in a near future

Individualizing Pharmacotherapy: Genetic factors and co-prescribed drugs affecting pharmacotherapy

Drug therapies may result in adverse drug reactions or in ineffective therapy. A better prediction which patients will not respond to drug therapy or will develop adverse drug reactions may avoid these events. In this thesis we studied the effect of drug-drug interactions and genetic variation. The exposure to potential life-threatening drug-drug interactions in the elderly general population (≥ 70 years) increased from 1.5 percent in 1992 to 2.9 percent in 2005. About half a percent of all hospital admissions were due to drug-drug interactions. The polymorphism rs622342 in the Organic Cation Transporter 1 and rs2289669 in the Multidrug And Toxin Extrusion 1 were both associated with the glucose lowering effect of metformin. The predictability of the response to metformin increased substantially if also the interaction between both polymorphisms was included. The CYP3A4*1B polymorphisms was associated with adverse drug reactions during simvastatin and atorvastatin therapy. This effect was stronger in women and in patients with the ABCB1 CT or TT genotype. These differences are most likely explained by a lower ABCB1 expression and a higher statin concentration in the hepatocyte. We also studied the association between genetic variation in the CYP2C9 gene and sulphonylurea response, the rs10494366 polymorphisms and sulphonylurea and calcium channel blocker response, genetic variation in the ABCB1 gene and the cholesterol lowering effect of simvastatin, and the association between the rs622342 polymorphism and the response to antiparkinson drugs. The response to drug therapy is better predictable if also the interaction between factors is taken into account

Trends in Occurrence and Phenotypic Resistance of Coagulase-Negative Staphylococci (CoNS) Found in Human Blood in the Northern Netherlands between 2013 and 2019

Background: For years, coagulase-negative staphylococci (CoNS) were not considered a cause of bloodstream infections (BSIs) and were often regarded as contamination. However, the association of CoNS with nosocomial infections is increasingly recognized. The identification of more than 40 different CoNS species has been driven by the introduction of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Yet, treatment guidelines consider CoNS as a whole group, despite increasing antibiotic resistance (ABR) in CoNS. This retrospective study provides an in-depth data analysis of CoNS isolates found in human blood culture isolates between 2013 and 2019 in the entire region of the Northern Netherlands. Methods: In total, 10,796 patients were included that were hospitalized in one of the 15 hospitals in the region, leading to 14,992 CoNS isolates for (ABR) data analysis. CoNS accounted for 27.6% of all available 71,632 blood culture isolates. EUCAST Expert rules were applied to correct for errors in antibiotic test results. Results: A total of 27 different CoNS species were found. Major differences were observed in occurrence and ABR profiles. The top five species covered 97.1% of all included isolates: S. epidermidis, S. hominis, S. capitis, S. haemolyticus, and S. warneri. Regarding ABR, methicillin resistance was most frequently detected in S. haemolyticus (72%), S. cohnii (65%), and S. epidermidis (62%). S. epidermidis and S. haemolyticus showed 50–80% resistance to teicoplanin and macrolides while resistance to these agents remained lower than 10% in most other CoNS species. Conclusion: These differences are often neglected in national guideline development, prompting a focus on ‘ABR-safe’ agents such as glycopeptides. In conclusion, this multi-year, full-region approach to extensively assess the trends in both the occurrence and phenotypic resistance of CoNS species could be used for evaluating treatment policies and understanding more about these important but still too often neglected pathogens

Inpatient prescribing of dual antiplatelet therapy according to the guidelines:a prospective intervention study

Background: In dual antiplatelet therapy (DAPT), low-dose acetylsalicylic acid is combined with a P2Y12 inhibitor. However, combining antithrombotic agents increases the risk of bleeding. Guidelines on DAPT recommend using this combination for a limited period of between three weeks and 30 months. This implies the risk of DAPT being erroneously continued after the intended stop date. Objective: The primary objective of this study is to assess the proportion of hospitalized patients treated with DAPT whose treatment deviated erroneously and unintentionally from the guidelines. We also assessed risk factors and the effect of a pharmacist intervention. Methods: All patients admitted to the Spaarne Gasthuis (Haarlem/ Hoofddorp, the Netherlands) who used DAPT between March 25th , 2019, and June 14th , 2019, were, in addition to receiving regular care, reviewed to assess whether their therapy was in line with the guidelines' recommendation and whether deviations were unintended and erroneous. In the event of an unintended deviation, the pharmacist intervened by contacting the prescriber by phone and giving advice to adjust the antithrombotic therapy in line with the guideline. Results: We included 411 patients, of whom 21 patients (5.1%) had a treatment that deviated from the guidelines. For 11 patients (2.7%), the deviation was unintended and erroneous. The major risk factor for erroneous deviation was the use of DAPT before hospital admission (OR 18.7; 95%Cl 4.79-72.7). In patients who used DAPT before admission, 18 out of 58 (31.0%) had a deviation from the guidelines of whom 8 (13.8%) were erroneous. For these eight patients, the pharmacist contacted the prescriber, and in these cases the therapy was adjusted in line with the guidelines. Conclusions: Adherence to the guidelines recommending DAPT was high within the hospital. However, patients who used DAPT before hospital admission had a higher risk of erroneous prescription of DAPT. Intervention by a pharmacist increased adherence to guidelines and may reduce the number of preventable bleeding cases

Development and validation of a tool to assess the risk of QT drug-drug interactions in clinical practice

Background The exact risk of developing QTc-prolongation when using a combination of QTc-prolonging drugs is still unknown, making it difficult to interpret these QT drug-drug interactions (QT-DDIs). A tool to identify high-risk patients is needed to support healthcare providers in handling automatically generated alerts in clinical practice. The main aim of this study was to develop and validate a tool to assess the risk of QT-DDIs in clinical practice. Methods A model was developed based on risk factors associated with QTc-prolongation determined in a prospective study on QT-DDIs in a university medical center inthe Netherlands. The main outcome measure was QTc-prolongation defined as a QTc interval > 450 ms for males and > 470 ms for females. Risk points were assigned to risk factors based on their odds ratios. Additional risk factors were added based on a literature review. The ability of the model to predict QTc-prolongation was validated in an independent dataset obtained from a general teaching hospital against QTc-prolongation as measured by an ECG as the gold standard. Sensitivities, specificities, false omission rates, accuracy and Youden's index were calculated. Results The model included age, gender, cardiac comorbidities, hypertension, diabetes mellitus, renal function, potassium levels, loop diuretics, and QTc-prolonging drugs as risk factors. Application of the model to the independent dataset resulted in an area under the ROC-curve of 0.54 (95% CI 0.51-0.56) when QTc-prolongation was defined as > 450/470 ms, and 0.59 (0.54-0.63) when QTc-prolongation was defined as > 500 ms. A cut-off value of 6 led to a sensitivity of 76.6 and 83.9% and a specificity of 28.5 and 27.5% respectively. Conclusions A clinical decision support tool with fair performance characteristics was developed. Optimization of this tool may aid in assessing the risk associated with QT-DDIs.Clinical Pharmacy and Toxicolog

Family size and intergenerational social mobility during the fertility transition: evidence of resource dilution from the city of Antwerp in nineteenth century Belgium

It has been argued in sociology, economics, and evolutionary anthropology that family size limitation enhances the intergenerational upward mobility chances in modernized societies. If parents have a large flock, family resources get diluted and intergenerational mobility is bound to head downwards. Yet, the empirical record supporting this resource dilution hypothesis is limited. This article investigates the empirical association between family size limitation and intergenerational mobility in an urban, late nineteenth century population in Western Europe. It uses life course data from the Belgian city of Antwerp between 1846 and 1920. Findings are consistent with the resource dilution hypothesis: after controlling for confounding factors, people with many children were more likely to end up in the lower classes. Yet, family size limitation was effective as a defensive rather than an offensive strategy: it prevented the next generation from going down rather than helping them to climb up the social ladder. Also, family size appears to have been particularly relevant for the middle classes. Implications for demographic transition theory are discussed

Drug-drug interactions with metronidazole and itraconazole in patients using acenocoumarol

PURPOSE: Various population-based cohort studies have shown that antimicrobial agents increase the risk of overanticoagulation in patients using coumarins. In this study, we assessed this association in hospitalized patients. METHODS: We included all patients hospitalized in the Spaarne Gasthuis (Haarlem/Hoofddorp, the Netherlands), who started using an antimicrobial agent during acenocoumarol treatment or vice versa between 1 January 2015 and 1 July 2019. Patients were followed from start of concomitant therapy until 48 h after termination of the concomitant therapy or discharge, whichever came first. We analyzed the association between the antimicrobial agents and the risk of overanticoagulation, defined as an interpolated INR above 6, using Cox regression analysis. We corrected for multiple testing with the Bonferroni correction. Patients who started using acenocoumarol and amoxicillin/clavulanic acid were used as reference group. RESULTS: In the study population, sixteen antimicrobial agents were started frequently concomitantly with acenocoumarol treatment. We included 2157 interaction episodes in 1172 patients. Patients who started using the combination of co-trimoxazole (HR 3.76; 95% CI 1.47-9.62; p = 0.006), metronidazole (HR 2.55; 95% CI 1.37-4.76; p = 0.003), or itraconazole (HR 4.11; 95% CI 1.79-9.45; p = 0.001) concomitantly with acenocoumarol treatment had an increased risk of overanticoagulation compared with patients using acenocoumarol and amoxicillin/clavulanic acid concomitantly. The associations for metronidazole (p = 0.045) and itraconazole (p = 0.015) remained statistically significant after correction for multiple testing. CONCLUSION: Co-trimoxazole, metronidazole, and itraconazole increase the risk of overanticoagulation in patients using acenocoumarol. These combinations should be avoided if possible or otherwise acenocoumarol doses should be reduced and INR measured more frequently

Comparison of two algorithms to support medication surveillance for drug-drug interactions between QTc-prolonging drugs

Background: QTc-prolongation is an independent risk factor for developing life-threatening arrhythmias. Risk management of drug-induced QTc-prolongation is complex and digital support tools could be of assistance. Bindraban et al. and Berger et al. developed two algorithms to identify patients at risk for QTc-prolongation. Objective: The main aim of this study was to compare the performances of these algorithms for managing QTcprolonging drug-drug interactions (QT-DDIs). Materials and Methods: A retrospective data analysis was performed. A dataset was created from QT-DDI alerts generated for inand outpatients at a general teaching hospital between November 2016 and March 2018. ECGs recorded within 7 days of the QT-DDI alert were collected. Main outcomes were the performance characteristics of both algorithms. QTc-intervals of > 500 ms on the first ECG after the alert were taken as outcome parameter, to which the performances were compared. Secondary outcome was the distribution of risk scores in the study cohort. Results: In total, 10,870 QT-DDI alerts of 4987 patients were included. ECGs were recorded in 26.2 % of the QT-DDI alerts. Application of the algorithms resulted in area under the ROC-curves of 0.81 (95 % CI 0.79-0.84) for Bindraban et al. and 0.73 (0.70-0.75) for Berger et al. Cut-off values of >= 3 and >= 6 led to sensitivities of 85.7 % and 89.1 %, and specificities of 60.8 % and 44.3 % respectively. Conclusions: Both algorithms showed good discriminative abilities to identify patients at risk for QTcprolongation when using >= 2 QTc-prolonging drugs. Implementation of digital algorithms in clinical decision support systems could support the risk management of QT-DDIs