Papers by Richard Koopmans
American Journal of Hypertension, 2009
nature publishing group articles G-protein-coupled receptors are important in cardiovascular phys... more nature publishing group articles G-protein-coupled receptors are important in cardiovascular physiology, e.g., by mediating effects of endogenous neurotransmitters and hormones such as noradrenaline, serotonin or angiotensin. The function of such receptors is regulated by Regulator of G-protein Signaling (RGS) proteins, which mostly dampen G-protein function by promoting the guanosine triphosphatase activity of their α-subunits. 2,3 Among the various RGS proteins, RGS2 seems to have a critical role in cardiovascular physiology. It is expressed in many cardiovascular tissues, including heart, kidney, and blood vessels. Silencing of the RGS2 gene enhances angiotensin II signaling. 9 Accordingly, RGS2 knockout mice are hypertensive and exhibit persistent constriction of the resistance vasculature, 10,11 whereas patients with Bartter's/Gitelman's syndrome have an enhanced expression of RGS2 and are hypotensive. 12 Thus, the overall effect of RGS2 appears to promote blood pressure lowering. The coding region of the RGS2 gene contains five exons which show genetic variation among subjects. While no coding polymorphisms were described in Caucasians, only one 1132C>A single-nucleotide polymorphism (SNP) was reported in black Americans 13 and nine (five nonsynonymous) in Japanese subjects, 14 including one which was demonstrated to affect RGS2 function. However, the promoter region, the introns and the noncoding parts of the exons of the RGS2 gene also contain several SNPs and insertion/deletion (I/D) polymorphisms, including one with demonstrated functional relevance. Their allelic frequency differs between ethnic groups, and some are exclusively found in one ethnicity. Two studies have explored possible associations between genetic heterogeneity within the RGS2 gene and the hypertensive phenotype. A study in Japanese subjects found an association of I/D 1891-1892TC (rs3053226) and 1026T>A (rs2746073) with hypertension (HT) in women but not men.
British Journal of Clinical Pharmacology, Feb 1, 2007
QTc interval-prolonging drugs have been linked to cardiac arrhythmias, cardiac arrest and sudden ... more QTc interval-prolonging drugs have been linked to cardiac arrhythmias, cardiac arrest and sudden death. In this study we aimed to quantify the risk of cardiac arrest associated with the use of non-antiarrhythmic QTc-prolonging drugs in an academic hospital setting. We performed a case-control study in which patients, for whom intervention of the advanced life support resuscitation team was requested for cardiac arrest between 1995 and 2003 in the Academic Medical Centre, Amsterdam, were compared with controls regarding current use of non-antiarrhythmic QTc-prolonging drugs. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, adjusting for potential confounding factors. A statistically significant increased risk of cardiac arrest (OR 2.1, 95% CI 1.2, 3.5) was observed in patients who received QTc-prolonging drugs (42/140). The risk was more pronounced in patients receiving doses > 1 defined daily dose (OR 2.5, 95% CI 1.1, 5.9), patients taking > 1 QTc-prolonging drug simultaneously (OR 4.8, 95% CI 1.6, 14) and patients taking pharmacokinetic interacting drugs concomitantly (OR 4.0, 95% CI 1.2, 13). Use of non-antiarrhythmic QTc-prolonging drugs in hospitalized patients with several underlying disease is associated with an increased risk of cardiac arrest. The effect is dose related and pharmacokinetic drug-drug interactions increase the risk substantially. Physicians caring for inpatients should be made aware of the fact that these non-antiarrhythmic drugs may be hazardous, so that potential risks can be weighed against treatment benefits and additional cardiac surveillance can be requested, if necessary. Noncardiac drugs and cardiac arrest
BMC Cardiovascular Disorders, Jun 2, 2010
Background: Genotype-phenotype association studies are typically based upon polymorphisms or hapl... more Background: Genotype-phenotype association studies are typically based upon polymorphisms or haplotypes comprised of multiple polymorphisms within a single gene. It has been proposed that combinations of polymorphisms in distinct genes, which functionally impact the same phenotype, may have stronger phenotype associations than those within a single gene. We have tested this hypothesis using genes encoding components of the renin-angiotensin-aldosterone system and the high blood pressure phenotype. Methods: Our analysis is based on 1379 participants of the cross-sectional SUNSET study randomly selected from the population register of Amsterdam. Each subject was genotyped for the angiotensinogen M235T, the angiotensinconverting enzyme insertion/deletion and the angiotensin II type 1 receptor A1166C polymorphism. The phenotype high blood pressure was defined either as a categorical variable comparing hypertension versus normotension as in most previous studies or as a continuous variable using systolic, diastolic and mean blood pressure in a multiple regression analysis with gender, ethnicity, age, body-mass-index and antihypertensive medication as covariates. Results: Genotype-phenotype relationships were explored for each polymorphism in isolation and for double and triple polymorphism combinations. At the single polymorphism level, only the A allele of the angiotensin II type 1 receptor was associated with a high blood pressure phenotype. Using combinations of polymorphisms of two or all three genes did not yield stronger/more consistent associations. We conclude that combinations of physiologically related polymorphisms of multiple genes, at least with regard to the renin-angiotensin-aldosterone system and the hypertensive phenotype, do not necessarily offer additional benefit in analyzing genotype/phenotype associations.
Journal of Human Hypertension, Aug 24, 2006
We sought to determine factors associated with hypertension awareness, pharmacological treatment ... more We sought to determine factors associated with hypertension awareness, pharmacological treatment and control among ethnic groups in Amsterdam, The Netherlands. We analysed data on hypertensive subjects (Dutch n ¼ 130, Hindustani n ¼ 115 and African Surinamese n ¼ 225). After adjustments for important covariates, hypertension awareness was more common in Dutch people with abdominal obesity and family history of hypertension (FHH). Abdominal obesity was also associated with higher level of awareness in African Surinamese. Female sex, FHH and recent physician (general practitioner (GP)) visit were associated with higher level of awareness in both African and Hindustani Surinamese. Among the Dutch, hypertension treatment was more common in those with abdominal obesity, FHH and GP visit. Among Hindustanis, female sex, abdominal obesity and GP visit were positively associated with treatment of hypertension. Old age, female sex, FHH and GP visit were positively associated, whereas smoking was negatively associated with lower treatment in African Surinamese. High education and more physical activity were associated with better blood pressure (BP) control, whereas obesity was associated with poor BP control among the Dutch. Among African Surinamese, female sex and FHH were associated with better BP control, whereas abdominal obesity was associated with poor BP control. Only old age was associated with poor BP control in Hindustanis. In conclusion, our findings indicate that more attention is needed in promoting awareness and treatment among those with lower hypertension risk (i.e., normal body weight people and those without FHH), those without recent GP visits in all ethnic groups and African and Hindustani Surinamese men and smokers. More effort is also needed in hypertension control among Dutch people with low education, obesity and inadequate physical activity, African Surinamese men and those without FHH and old Hindustani people.
Hypertension, Feb 1, 2005
Renal dysfunction is an important cause of morbidity and mortality in patients with malignant hyp... more Renal dysfunction is an important cause of morbidity and mortality in patients with malignant hypertension. Microangiopathic hemolysis (MAHA) related to malignant hypertension may cause renal insufficiency by obstruction of interlobular arteries. We hypothesized that the presence of MAHA is an important indicator of renal dysfunction and recovery in malignant hypertension. We retrospectively analyzed 97 patients admitted between April 1994 and April 2004 with malignant hypertension. MAHA was defined as a low platelet count (Ͻ150ϫ10 9 /L) with either an elevated lactic dehydrogenase (Ͼ220 U/L) or presence of schistocytes. MAHA was present in 26 of 97 patients (27%). Serum creatinine levels at admission were significantly higher in those with than in those without MAHA: median serum creatinine 690 mol/L (interquartile range [IQR] 394 to 1105) and 120 mol/L (IQR 82 to 211), respectively (PϽ0.01). Macroalbuminuria was present in 88% with versus 41% without MAHA (PϽ0.01). Patients with MAHA were more often black (73%; PϽ0.01) and had higher systolic blood pressure (mean 242 mm Hg versus 225 mm Hg; PϽ0.01). Dialysis was needed in 15 patients with MAHA (58%) versus 2 patients (3%) without MAHA. In 6 patients with MAHA, dialysis could be stopped. Cox regression analysis showed that MAHA and systolic blood pressure were the most important indicators of renal improvement during follow-up, with a hazard ratio of 0.24 (95% confidence interval [CI], 0.08 to 0.75; Pϭ0.01) and 1.02 per mm Hg increase in systolic blood pressure (95% CI, 1.01 to 1.05; Pϭ0.01). In conclusion, MAHA is an important indicator of renal insufficiency and recovery in patients with malignant hypertension. (Hypertension. 2005;45:246-251.
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Antimicrobial Agents and Chemotherapy, 1997
The influence of food intake on the pharmacokinetics of artemisinin was studied with six healthy ... more The influence of food intake on the pharmacokinetics of artemisinin was studied with six healthy Vietnamese male subjects. In a crossover study, artemisinin capsules (500 mg) were administered with and without food after an overnight fast. Plasma samples were obtained up to 24 h after intake of each drug. Measurement of artemisinin concentrations was performed by high-performance liquid chromatography with electrochemical detection. Tolerance was evaluated according to subjective and objective findings, including repeated physical examinations, routine blood investigations, and electrocardiograms. Pharmacokinetics were analyzed with a noncompartmental method and with a one-compartment model. This model had either zero-order or first-order input. No statistically significant differences were found between the results of the two experimental conditions. Specifically, there were no consistent differences in parameters most likely to be affected by food intake, including absorption prof...
The American Journal of Tropical Medicine and Hygiene, 1999
Eight healthy Vietnamese male subjects received 400 mg artemisinin formulated into fatty supposit... more Eight healthy Vietnamese male subjects received 400 mg artemisinin formulated into fatty suppositories (FS), and six different subjects received 500 mg of artemisinin formulated in polyethylene glycol suppositories (PEGS). Plasma concentrations were measured by high-performance liquid chromatography with electrochemical detection; concentration versus time curves were analyzed with nonparametric methods. No statistically significant differences were found between the two formulations. The maximum concentration (Cmax) was 100 Ϯ 102 g/L (mean Ϯ SD, range ϭ 24-330) g/L (FS), the pharmacokinetic lag time (Tlag) was 1.3 Ϯ 1.0 hr (range ϭ 0-3) (FS), and the time of the maximum concentration (Tmax) was 7.1 Ϯ 2.1 hr (range ϭ 3-10) hr (FS). Because artemisinin is not available for intravenous dosage, absolute bioavailability cannot be assessed. However, compared with a previous study on oral artemisinin in healthy Vietnamese subjects, bioavailability relative to oral administration was estimated to be approximately 30%. We conclude that therapeutic blood concentrations of artemisinin can be reached after rectal dosage. The dose after rectal administration should probably be higher than after oral administration; doubling or tripling the oral dose might be necessary, which would imply a rectal dose of at least 20 mg/kg of body weight given twice a day.
The American Journal of Tropical Medicine and Hygiene, 2002
The assumed metabolic breakdown of albendazole by mucosal CYP3A4 enzymes was studied by coadminis... more The assumed metabolic breakdown of albendazole by mucosal CYP3A4 enzymes was studied by coadministering albendazole (10 mg/kg) with grapefruit juice. Concentrations of albendazole sulfoxide (ABZSX), the active metabolite of albendazole, were compared with those after albendazole was administered with water, a fatty meal, or grapefruit juice plus cimetidine (10 mg/kg). In comparison to water, maximum ABZSX concentration (C max ) was enhanced 6.5-fold by a fatty meal (from 0.24 ± 0.09 mg/l to 1.55 ± 0.30 mg/l; mean ± SD; P < 0.001) and 3.2-fold by grapefruit juice (from 0.24 ± 0.09 mg/l to 0.76 ± 0.37 mg/L; P ס 0.031). When grapefruit juice was combined with cimetidine, C max was significantly lower than with grapefruit juice alone (0.41 ± 0.29 mg/l and 0.76 ± 0.37 mg/l, respectively; P ס 0.022). The area under the concentration-time curve from 0 to infinity (AUC 0-⍀ ) followed a comparable pattern. Half-life (T 1/2 ) was 8.8 ± 4.2 hr and 8.2 ± 4.3 hr after administration with water or a fatty meal (P ס 1.000). Grapefruit juice shortened T 1/2 by 46% (P ס 0.026). We hypothesize that albendazole is metabolized by CYP3A4 enzymes in the intestinal mucosa. This process can be inhibited by grapefruit juice. Cimetidine decreased albendazole bioavailability.
American journal of hypertension, 2009
The success of antihypertensive drugs may be improved by better prediction of their efficacy in i... more The success of antihypertensive drugs may be improved by better prediction of their efficacy in individual patients. The objective of our study was to determine whether genetic variation predicts the individual systolic blood pressure (SBP) response to antihypertensive drugs and to assess to what extent the individual treatment response could be explained by the combined effects of known demographic, environmental, and genetic factors. A population-based, crossover, open-label randomized treatment study stratified for ethnicity in 102 mildly hypertensive patients aged 35-60 years in an outpatient hypertension clinic (the ROTATE study). Patients underwent five successive 6-week treatment episodes of single-drug treatment in a randomized order with representatives of the major antihypertensive drug classes. The primary outcome measure was the DeltaSBP after 6-week drug therapy. Participants (n = 97) completed 407 treatment episodes. The estimated unpredictable natural variation of SBP...
American journal of hypertension, 2009
Polymorphisms in the Regulator of G-protein Signaling 2 (RGS2) gene have been reported to be asso... more Polymorphisms in the Regulator of G-protein Signaling 2 (RGS2) gene have been reported to be associated with hypertension (HT) in Japanese women and black Americans of either gender but not in white Americans or Japanese men. We have tested whether these proposed ethnicity- and gender-specific associations between RGS2 gene polymorphisms and HT can be confirmed in an independent population of male and female blacks, whites, and south Asians. A population-based sample of 1379 black, white Dutch, and south Asian subjects from the Amsterdam area was genotyped for eight polymorphisms in the RGS2 gene. All analyses were done separately per ethnic group. The phenotype high blood pressure was defined as a dichotomous variable comparing HT vs. normotension (NT) and as a linear variable using systolic blood pressure (SBP) in a multiple regression analysis with concomitant antihypertensive medication, age and body mass index as coexplanatory variables. Ethnic differences in the frequency of p...
Clinical Pharmacology & Therapeutics, 2008
Despite initial enthusiasm, 1-3 the use of pharmacogenetics has remained limited to investigation... more Despite initial enthusiasm, 1-3 the use of pharmacogenetics has remained limited to investigation in only a few clinical fields such as oncology and psychiatry. The main reason is the paucity of scientific evidence to show that pharmacogenetic testing leads to improved clinical outcomes. 9,10 Moreover, for most pharmacogenetic tests (such as tests for genetic variants of cytochrome P450 enzymes) a detailed knowledge of pharmacology is a prerequisite for application in clinical practice, and both physicians and pharmacists might find it difficult to interpret the clinical value of pharmacogenetic test results. Guidelines that link the result of a pharmacogenetic test to therapeutic recommendations might help to overcome these problems, but such guidelines are only sparsely available. In 2001, an early step was taken to develop such guidelines for the therapeutic use of antidepressants, and these included CYP2D6-related dose recommendations drawn from pharmacokinetic study data. 11 However, the use of such recommendations in routine clinical practice remains difficult, because they are currently outside the ambit of the clinical environment and are not accessible during the decision-making process by physicians and pharmacists, namely the prescription and dispensing of drugs.
Pharmacogenetics, 2003
The extent of blood pressure lowering by anti-hypertensive agents is difficult to predict for ind... more The extent of blood pressure lowering by anti-hypertensive agents is difficult to predict for individual patients, even when evaluated in the context of biochemical or demographic information. Genetic predictors (mainly single nucleotide polymorphisms, SNPs) have been the focus of several recent studies and are gaining much attention. We have conducted a literature search for studies in which the lowering of ambient blood pressure by specific drugs or drug classes in humans was related to specific genotypes. Twenty-eight studies were identified, of which six had a single-dose design, and the remaining 22 studied drug effects after more than 4 weeks of drug administration. Virtually all were association studies. Prospective trials that compared the prognostic value of genetic methods to routine clinical practice were not identified. Almost all studies used a candidate-gene design, usually with a very small number of SNPs (typically one). Gene-gene and gene-environment interactions were studied only rarely. Only one study targeted genes involved in drug metabolism. Most candidate-genes were part of the renin-angiotensin system. By far the most extensively studied has been the angiotensin-converting enzyme insertion/deletion polymorphism (15 studies) but, to date, no clear picture has emerged for this or other genetic variants. Thus, the potential for utility of genetic characterization of individual patients as a predictor of anti-hypertensive response has yet to be realized.
Hypertension, 2004
Renal dysfunction is an important cause of morbidity and mortality in patients with malignant hyp... more Renal dysfunction is an important cause of morbidity and mortality in patients with malignant hypertension. Microangiopathic hemolysis (MAHA) related to malignant hypertension may cause renal insufficiency by obstruction of interlobular arteries. We hypothesized that the presence of MAHA is an important indicator of renal dysfunction and recovery in malignant hypertension. We retrospectively analyzed 97 patients admitted between April 1994 and April 2004 with malignant hypertension. MAHA was defined as a low platelet count (<150×10 9 /L) with either an elevated lactic dehydrogenase (>220 U/L) or presence of schistocytes. MAHA was present in 26 of 97 patients (27%). Serum creatinine levels at admission were significantly higher in those with than in those without MAHA: median serum creatinine 690 μmol/L (interquartile range [IQR] 394 to 1105) and 120 μmol/L (IQR 82 to 211), respectively ( P <0.01). Macroalbuminuria was present in 88% with versus 41% without MAHA ( P <0.01...
European Heart Journal, 2008
Familial hypercholesterolaemia (FH) is characterized by premature coronary heart disease (CHD). H... more Familial hypercholesterolaemia (FH) is characterized by premature coronary heart disease (CHD). However, the incidence of CHD varies considerably among FH patients. Genetic variation in the renin -angiotensin-aldosterone system (RAAS) and the adrenalin/noradrenalin system may be of importance in determining the CHD risk in FH, because of their involvement in CHD. We investigated the association between CHD risk and combined genetic variation in the RAAS and adrenalin/noradrenalin system. In 2190 FH patients, we genotyped six RAAS polymorphisms and five adrenalin/noradrenalin polymorphisms. For each patient, we calculated two gene-load scores by counting the number of risk genotypes within each pathway. Four of the six RAAS polymorphisms and none of the polymorphisms in the adrenalin/noradrenalin system were significantly associated with CHD (P , 0.05). The RAAS gene-load score was significantly associated with CHD (P linear trend , 0.001): in patients with a gene-load score of 5 or 6, the CHD risk was 2.3 times as high as in patients with a score of 0 or 1. The gene-load score of the adrenalin/noradrenalin system was not associated with CHD. Genetic variation in the RAAS contributes gene-dose dependently to CHD risk in patients with FH, whereas genetic variation in the adrenalin/noradrenalin system is not associated with CHD.
Circulation, 2006
Background— We previously hypothesized that high activity of creatine kinase, the central regulat... more Background— We previously hypothesized that high activity of creatine kinase, the central regulatory enzyme of energy metabolism, facilitates the development of high blood pressure. Creatine kinase rapidly provides adenosine triphosphate to highly energy-demanding processes, including cardiovascular contraction, and antagonizes nitric oxide–mediated functions. Relatively high activity of the enzyme, particularly in resistance arteries, is thought to enhance pressor responses and increase blood pressure. Tissue creatine kinase activity is reported to be high in black people, a population subgroup with greater hypertension risk; the proposed effects of high creatine kinase activity, however, are not “race dependent.” We therefore assessed whether creatine kinase is associated with blood pressure in a multiethnic population. Methods and Results— We analyzed a stratified random sample of the population of Amsterdam, the Netherlands, consisting of 1444 citizens (503 white European, 292 S...
Cancer Treatment Reviews, 1997
BMC Cardiovascular Disorders, 2010
Background Genotype-phenotype association studies are typically based upon polymorphisms or haplo... more Background Genotype-phenotype association studies are typically based upon polymorphisms or haplotypes comprised of multiple polymorphisms within a single gene. It has been proposed that combinations of polymorphisms in distinct genes, which functionally impact the same phenotype, may have stronger phenotype associations than those within a single gene. We have tested this hypothesis using genes encoding components of the renin-angiotensin-aldosterone system and the high blood pressure phenotype. Methods Our analysis is based on 1379 participants of the cross-sectional SUNSET study randomly selected from the population register of Amsterdam. Each subject was genotyped for the angiotensinogen M235T, the angiotensin-converting enzyme insertion/deletion and the angiotensin II type 1 receptor A1166C polymorphism. The phenotype high blood pressure was defined either as a categorical variable comparing hypertension versus normotension as in most previous studies or as a continuous variabl...
American Journal of Hypertension, 2013
Cardiac and cerebrovascular events in hypertensive patients are related to specific features of t... more Cardiac and cerebrovascular events in hypertensive patients are related to specific features of the 24-hour diurnal blood pressure (BP) profile (i.e., daytime and nighttime BP, nocturnal dip (ND), and morning surge (MS)). This investigation aimed to characterize 24-hour diurnal systolic BP (SBP) with parameters that correlate directly with daytime and nighttime SBP, ND, and MS using nonlinear mixed effects modeling. methods Ambulatory 24-hour SBP measurements (ABPM) of 196 nontreated subjects from three ethnic groups were available. A population model was parameterized in NONMEM to estimate and evaluate the parameters baseline SBP (BSL), nadir (minimum SBP during the night), and change (SBP difference between day and night). Associations were tested between these parameters and patient-related factors to explain interindividual variability. The diurnal SBP profile was adequately described as the sum of 2 cosine functions. The following typical values (interindividual variability) were found: BSL = 139 mm Hg (11%); nadir = 122 mm Hg (14%); change = 25 mm Hg (52%), and residual error = 12 mm Hg. The model parameters correlate well with daytime and nighttime SBP, ND, and MS (R 2 = 0.50-0.92). During covariate analysis, ethnicity was found to be associated with change; change was 40% higher in white Dutch subjects and 26.8% higher in South Asians than in blacks. The developed population model allows simultaneous estimation of BSL, nadir, and change for all individuals in the investigated population, regardless of individual number of SBP measurements. Ethnicity was associated with change. The model provides a tool to evaluate and optimize the sampling frequency for 24-hour ABPM.
Comprehensive Learning Effects of a Course on Patient Safety
Background: Improving patient safety is an extremely relevant topic in medicine. Training may con... more Background: Improving patient safety is an extremely relevant topic in medicine. Training may contribute to limiting unsafety, but effects are often only evaluated on the lower levels of learning as defined by Kirkpatrick. Summary of work: Effects of a course 'Patient Safety' for residents[for full text, please go to the a.m. URL]
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Papers by Richard Koopmans