Drug Safety Unit

The Hague, Netherlands

Drug Safety Unit

The Hague, Netherlands

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Ruiter R.,Erasmus University Rotterdam | Ruiter R.,Drug Safety Unit | Visser L.E.,Erasmus University Rotterdam | van Duijn C.M.,Erasmus University Rotterdam | And 2 more authors.
Current Cancer Drug Targets | Year: 2011

The renin-angiotensin system (RAS) plays an important role in the regulation of the cardiovascular system. In addition to RAS enzymes in plasma, the RAS is present in various local organ systems. Moreover, local expression of the RAS has been shown in various malignant cells. In 1990, an insertion/deletion (I/D) polymorphism in the ACE gene was discovered, accounting for half of the variance of the serum ACE enzyme levels. Serum ACE concentrations were significantly higher in homozygotes with the shorter deletion allele (DD) than in heterozygotes (ID) or in homozygotes with the longer insertion allele (II). Since 2000, twentyfour studies have been published hypothesizing an association between the ACE I/D polymorphism and cancer risk. This review focuses on the insertion/deletion polymorphism in the ACE gene in association with the risk of cancer and consequently on its potential role as therapeutic drug target in cancer. Furthermore a meta-analysis of the published studies was performed. Fourteen statistically non-significant studies were found, as well as ten studies with a statistically significant finding. The results of the meta-analyses performed were not consistent. However, both methods (one based on the Fisher p-value, and one on inverse variance weighted meta-analysis), indicated a (nearly) statistically significantly decreased risk in carriers of the II genotype in comparison to the DD genotype with regard to risk of prostate cancer and risk of (postmenopausal) breast cancer. Nevertheless, results show a large variation and are often contradictory. As this may be partly explained by a lack of power, genotyping techniques, and choice of study population, it is expected that future studies will shed more light on these associations. © 2011 Bentham Science Publishers Ltd.


Ruiter R.,Erasmus University Rotterdam | Ruiter R.,Drug Safety Unit | Visser L.E.,Erasmus University Rotterdam | Vn Herk-Sukel M.P.P.,PHARMO Institute for Drug Outcomes Research | And 9 more authors.
Diabetologia | Year: 2012

Aims/hypothesis Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study. Methods Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes. Results Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified. Conclusion/interpretation Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin. © 2011 The Author(s).


Ruiter R.,Erasmus University Rotterdam | Ruiter R.,Drug Safety Unit | Visser L.E.,Erasmus University Rotterdam | Van Herk-Sukel M.P.P.,PHARMO Institute for Drug Outcomes Research | And 9 more authors.
Diabetes Care | Year: 2012

OBJECTIVE - Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives. RESEARCH DESIGN AND METHODS - Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. RESULTS - Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 [95% CI 0.88-0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives. CONCLUSIONS - In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated. © 2012 by the American Diabetes Association.


Teichert M.,Erasmus Medical Center | Teichert M.,Scientific Institute Dutch Pharmacists | van Noord C.,Erasmus Medical Center | Uitterlinden A.G.,Erasmus Medical Center | And 7 more authors.
British Journal of Haematology | Year: 2011

In the Netherlands, several reports have described a potentiation of acenocoumarol-induced anticoagulation by co-medication of omeprazole or esomeprazole and competitive inhibition of CYP2C19 has been suggested as a possible mechanism for this interaction. We conducted an observational cohort study to investigate the effects of various proton pump inhibitors (PPIs) on acenocoumarol effectiveness. All 2755 subjects from the Rotterdam Study who received acenocoumarol maintenance treatment between April 1st, 1991 and September 9th, 2009 were followed for events of an international normalized ratio (INR)≥6, until death, end of treatment, or end of the study period. The Andersen-Gill extension of the Cox proportional hazards model was used to calculate risks for repeated events of overanticoagulation in relation to concomitant PPI use. The risk for overanticoagulation was most pronounced for esomeprazole (HR 1·99, 95% CI 1·55-2·55) and lansoprazole (HR 1·49, 95% CI 1·05-2·10). There was also a lower and non-significant risk increase for the other PPIs. We did not detect a modification of these results by CYP2C19*2 genotype. Caution should be paid to co-medication with esomeprazole and lansoprazole during acenocoumarol treatment and possibly also with other PPIs. © 2011 Blackwell Publishing Ltd.


Teichert M.,Erasmus Medical Center | Teichert M.,Scientific Institute Dutch Pharmacists | Eijgelsheim M.,Erasmus Medical Center | Uitterlinden A.G.,Erasmus Medical Center | And 7 more authors.
Pharmacogenetics and Genomics | Year: 2011

Background: Genome-wide association studies (GWAS) on warfarin and acenocoumarol showed that interindividual dosage variation is mainly associated with single nucleotide polymorphisms (SNPs) in VKORC1 and to a lesser extent in CYP2C9 and CYP4F2. For phenprocoumon dosage, the genes encoding CYP3A4 and ApoE might play a role. OBJECTIVE: To assess the association between common genetic variants within VKORC1, CYP2C9, CYP4F2, CYP3A4, and ApoE and phenprocoumon maintenance dosage, and to identify novel signals using GWAS. METHODS: We selected all participants from the Rotterdam study who were treated with phenprocoumon. For each SNP, we tested the association between the above-mentioned genotypes and age, sex, body mass index, and target INR adjusted-phenprocoumon maintenance dosage. Results: Within our study population (N=244), VKORC1, CYP2C9, CYP4F2 genotypes together explained 46% of phenprocoumon maintenance dosage variation. Each additional VKORC1 variant allele reduced phenprocoumon maintenance dosage by 4.8 mg/week (P<0.0001) and each additional CYP2C9 variant allele by 2.2 mg/week (P=0.002). Each additional variant allele of CYP4F2 increased phenprocoumon dosage by 1.5 mg/week (P=0.022). Variant alleles of CYP3A41*B and ApoE showed no association with phenprocoumon dosage. Genome-wide significant SNPs were all related to VKORC1 activity. Best associated were two SNPs in complete linkage disequilibrium with each other and with SNPs within VKORC1: rs10871454 [Syntaxin 4A (STX4A)] and rs11150604 (ZNF646), each with a P value of 2.1×10- 22. Each reduced phenprocoumon maintenance dosage weekly by 4.9 mg per variant allele. Conclusion: Similar to earlier findings with warfarin and acenocoumarol, phenprocoumon maintenance dosage depended on polymorphisms in the VKORC1 gene. CYP2C9 and CYP4F2 were of modest relevance. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Van Blijderveen J.C.,Erasmus Medical Center | Straus S.M.,Erasmus Medical Center | Zietse R.,Erasmus Medical Center | Stricker B.H.,Erasmus Medical Center | And 3 more authors.
International Urology and Nephrology | Year: 2014

Purpose: Because most population-based studies on the epidemiology of chronic kidney disease (CKD) are cross-sectional, there is, except for end-stage renal disease, hardly any information on incidence rates. Methods: We conducted a retrospective cohort study in a dynamic population, using data of 784,563 adult participants retrieved from the Integrated Primary Care Information database, a primary care database containing the complete electronic longitudinal medical records. CKD (both incidence and prevalence) was based on (1) an increased urine albumin-to-creatinine ratio, (2) a decreased estimated glomerular filtration rate, or (3) explicit statement in the medical record. Results were stratified by age according to the WHO standard population, sex, and diabetes mellitus. Results: Based on a single measurement only, the incidence rate of CKD in adults was 1,213 per 100,000 person-years, and 6.7 percent of the adult population had a prevalent diagnosis of CKD. The incidence rate increased by age and was the highest in participants with diabetes with an incidence of 25,000 per 100,000 person-years, affecting over 75 percent of participants with diabetes. Conclusions: This is the first study to report the incidence rates of all stages of CKD for the entire adult population, stratified by sex, 5-year age groups, and diabetes. Our data demonstrate that the incidence of CKD increases with age and is the highest in participants with diabetes mellitus. © 2013 Springer Science+Business Media.


Van Den Hondel K.E.,Erasmus University Rotterdam | Eijgelsheim M.,Erasmus University Rotterdam | Ruiter R.,Erasmus University Rotterdam | Ruiter R.,Drug Safety Unit | And 5 more authors.
Heart | Year: 2011

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of heart failure. NSAIDs inhibit the synthesis of renal prostaglandin, which results in a higher total blood volume, cardiac output and preload. The association between recent start of NSAIDs in elderly people and echocardiographic parameters was investigated. Methods: In the Rotterdam Study, a population-based cohort study, the effect of NSAIDs on left ventricular end-systolic dimension, left ventricular end-diastolic dimension, fractional shortening and left ventricular systolic function was studied in all participants for whom an echocardiogram was available (n=5307). NSAID use was categorised as current NSAID use on the date of echocardiography, past use and never used before echocardiography during the study period. Current use was divided into short-term NSAID use (≤14 days) and long-term NSAID use (>14 days). Associations between drug exposure and echocardiographic measurements were assessed using linear and logistic regression analyses. Results: Current NSAID use for <14 days was associated with a significantly higher left ventricular endsystolic dimension (+1.74 mm, 95% CI 0.20 to 3.28), left ventricular end-diastolic dimension (+3.69 mm, 95% CI 1.08 to 6.31) and significantly lower fractional shortening (-6.03%, 95% CI -9.81% to -2.26%) compared with non-users. Current NSAID use for >14 days was associated with a higher left end-diastolic dimension (+1.96 mm, 95% CI 0.82 to 3.11) but there was no change in the other echocardiographic parameters. Conclusion: This study is the first to investigate the association between NSAIDs and echocardiographic parameters and suggests that there is a transient effect of short-term use of NSAIDs on the left ventricular dimension and function of the heart.


Liamis G.,Erasmus Medical Center | Rodenburg E.M.,Erasmus Medical Center | Rodenburg E.M.,Drug Safety Unit | Hofman A.,Erasmus Medical Center | And 4 more authors.
American Journal of Medicine | Year: 2013

Background: Electrolyte disorders have been studied mainly in hospitalized patients, whereas data in the general population are limited. The aim of this study was to determine the prevalence and risk factors of common electrolyte disorders in older subjects recruited from the general population. Methods: A total of 5179 subjects aged 55 years or more were included from the population-based Rotterdam Study. We focused on hyponatremia, hypernatremia, hypokalemia, hyperkalemia, and hypomagnesemia. Multivariable logistic regression was used to study potential associations with renal function, comorbidity, and medication. The adjusted mortality also was determined for each electrolyte disorder. Results: A total of 776 subjects (15.0%) had at least 1 electrolyte disorder, with hyponatremia (7.7%) and hypernatremia (3.4%) being most common. Diabetes mellitus was identified as an independent risk factor for hyponatremia and hypomagnesemia, whereas hypertension was associated with hypokalemia. Diuretics were independently associated with several electrolyte disorders: thiazide diuretics (hyponatremia, hypokalemia, hypomagnesemia), loop diuretics (hypernatremia, hypokalemia), and potassium-sparing diuretics (hyponatremia). The use of benzodiazepines also was associated with hyponatremia. Hyponatremic subjects who used both thiazides and benzodiazepines had a 3 mmol/L lower serum sodium concentration than subjects using 1 or none of these drugs (P <.001). Hyponatremia and hypomagnesemia were independently associated with an increased mortality risk. Conclusions: Electrolyte disorders are common among older community subjects and mainly associated with diabetes mellitus and diuretics. Subjects who used both thiazides and benzodiazepines had a more severe degree of hyponatremia. Because even mild electrolyte disorders were associated with mortality, monitoring of electrolytes and discontinuation of offending drugs may improve outcomes. © 2013 Elsevier Inc.


Becker M.L.,Erasmus University Rotterdam | Becker M.L.,Hospital Pharmacy | Elens L.L.F.S.,Erasmus University Rotterdam | Visser L.E.,Erasmus University Rotterdam | And 7 more authors.
Pharmacogenomics Journal | Year: 2013

Several statins are substrates for the multidrug resistance-associated protein 2 transporter, encoded by the ABCC2 gene. We analyzed in the Rotterdam Study whether the common polymorphisms -24C>T, 1249G>A and 3972C>T in the ABCC2 gene were associated with a dose decrease or switch to another cholesterol-lowering drug in simvastatin and atorvastatin users. These events could indicate an adverse effect or a too strong reduction in cholesterol level. We identified 1014 simvastatin and atorvastatin users during the period 1 January 1991 to 1 January 2010. Associations between genetic variation and the risk of these events were analyzed using Cox proportional hazards modelling. The ABCC2 -24C>T genotype (HR 1.32 95% CI 1.04-1.69) and the H12 haplotype versus the H2 haplotype (HR 1.49; 95% CI 1.06-2.09) were associated with these events in simvastatin users. A similar but not significant association was found in atorvastatin users. To conclude, genetic variation in the ABCC2 gene is associated with these events in simvastatin users. © 2013 Macmillan Publishers Limited. All rights reserved 1470-269X/13.


Van Blijderveen J.C.,Erasmus Medical Center | Straus S.M.,Erasmus Medical Center | Rodenburg E.M.,Erasmus Medical Center | Zietse R.,Erasmus Medical Center | And 4 more authors.
American Journal of Medicine | Year: 2014

Background Chlorthalidone and hydrochlorothiazide are often considered as interchangeable. However, greater (nighttime) blood pressure reduction, and alleged pleiotropic effects have renewed the interest in chlorthalidone. A recent study showed an increased risk of adverse events with chlorthalidone, including hyponatremia. Methods To investigate differences in risk of hyponatremia between chlorthalidone and hydrochlorothiazide, adjusted for daily dose, we conducted a population-based case-control study within the Dutch IPCI (Integrated Primary Care Information) database. The study population included all subjects ≥18 years without diabetes mellitus, heart failure, liver failure, and malignancy, who were registered in the IPCI database from 1996 to 2011. Cases were subjects with a serum sodium <130 millimoles per liter or hospitalization due to hyponatremia. Controls were matched on practice, age within 5 years, sex, and date of onset. Results A total of 1033 cases of hyponatremia were identified. Hyponatremia was more common with chlorthalidone than with hydrochlorothiazide at equal dose per day: adjusted odds ratio was 2.09 (95% confidence interval [CI], 1.13-3.88) for 12.5 milligrams per day and 1.72 (95% CI, 1.15-2.57) for 25 milligrams per day. Risks were not significantly increased with chlorthalidone compared with twice the dose per day of hydrochlorothiazide. Conclusions This is the first study that shows an increased risk of hyponatremia with chlorthalidone relative to hydrochlorothiazide at equal milligram-to-milligram dose per day. The need for a lower dose of chlorthalidone than hydrochlorothiazide to achieve similar blood pressure reduction likely compensates for the increased risk of hyponatremia at equal dose © 2014 Elsevier Inc. All rights reserved.

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