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Harderwijk, Netherlands

van der Weide K.,St Jansdal Hospital
Pharmacogenomics Journal | Year: 2016

Prescription of clozapine is complicated by the occurrence of clozapine-induced reduction of neutrophils. The aim of this study was to identify genetic risk factors in a population of 310 Dutch patients treated with clozapine, including 38 patients developing neutropenia and 31 patients developing agranulocytosis. NQO2 1541AA (NRH quinone oxidoreductase 2; protects cells against oxidative metabolites) was present at a higher frequency in agranulocytosis patients compared with control (23% versus 7%, P=0.03), as was ABCB1 (ABC-transporter-B1; drug efflux transporter) 3435TT (32% versus 20%, P=0.05). In patients developing neutropenia, ABCB1 3435TT and homozygosity for GSTT1null (glutathione-S-transferase; conjugates reactive clozapine metabolites into glutathione) were more frequent compared with control (34% versus 20%, P=0.05 and 31% versus 14%, P=0.03), whereas GSTM1null was less frequent in these patients (31% versus 52%, P=0.03). To investigate whether combinations of the identified genetic risk factors have a higher predictive value, should be confirmed in a larger case–control study.The Pharmacogenomics Journal advance online publication, 10 May 2016; doi:10.1038/tpj.2016.32. © 2016 Macmillan Publishers Limited

ten Dam E.,University of Groningen | van der Heijden P.,St Jansdal Hospital | Korsten-Meijer A.G.W.,University of Groningen | Goorhuis-Brouwer S.M.,University of Groningen
International Journal of Pediatric Otorhinolaryngology | Year: 2013

Objectives: To evaluate the frequency of submucous cleft palate (SMCP) in a group of children with clefts. The reason for suspecting submucous cleft, age of diagnosis, effect of age on speech development, problems in speech, hearing and swallowing were compared with previous literature. Methods: Retrospective chart review: Out of 33 patients with SMCP, registered by the Groninger cleft team over approximately 20 years (1990 until July 2012), 28 non-syndromic patients with a proven diagnosis of SMCP were included: 17 males and 11 females. Speech and hearing were examined and the number of patients with SMCP and age at time of diagnosis were evaluated. The percentages of problems in resonance, articulation and hearing, present at time of diagnosis, were compared with the percentages of problems found after surgery. Results: Out of 800 patients with clefts, 28 patients (3,5%) were diagnosed with SMCP at a mean age of 3;9 years. All patients presented one or more symptomatic complaints at time of diagnosis: hypernasality (65%), problems in articulation (46%), conductive hearing loss (39%) and/or swallowing problems (32%). A bifid uvula was found in 92%. Following surgery, hypernasal speech and swallowing problems were no longer observed. The articulation problems remained after surgery. Age of diagnosis seems no predictor of articulation problems. An improvement in hearing was observed but normal hearing was not achieved. Pharyngoplasty appeared to be a successful and save treatment of hypernasality. Conclusions: SMCP is a rare cleft palate which is, despite the presence of a bifid uvula and symptoms of velopharyngeal insufficiency, often diagnosed late. In children with a bifid uvula and mild problems in speech, hearing and swallowing, it is important to be alert to SMCP because SMCP may account for these persistent mild complaints. Therefore, early detecting of SMCP can yield profits. © 2013 Elsevier Ireland Ltd.

Van Der Weide K.,St Jansdal Hospital | Van Der Weide J.,St Jansdal Hospital
Journal of Clinical Psychopharmacology | Year: 2014

BACKGROUND: Besides dietary, hormonal, or pathological factors, mutations in cytochrome P450 enzymes are thought to be responsible for the interindividual differences in serum concentrations of cytochrome P450 (CYP450)-dependent drugs. Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of greater than 50% of the prescribed drugs. Recently, a new single-nucleotide polymorphism (SNP) was found (CYP3A4*22), which results in a decreased enzyme activity, in contrast to the other known SNPs in CYP3A4. We investigated to which degree the CYP3A4*22 SNP affects serum concentrations of patients receiving quetiapine, a drug exclusively metabolized by CYP3A4. METHODS: Two hundred thirty-eight adult patients receiving quetiapine were included in this study, based on availability of DNA, serum quetiapine levels, and information on dose. Patients were genotyped for CYP3A4*22 using allele-specific polymerase chain reaction, and, as a control, restriction fragment length polymorphism analysis. RESULTS: Carriers of the CYP3A4*22 allele (*1/*22 and *22/*22, n = 31) had 2.5-fold higher serum levels of quetiapine than did wild-type patients (n = 207; P = 0.03) when using a comparable dose (median, 300 mg/d for both wild-type and carriers; P = 0.67). The dose-corrected serum concentration (C/D) was 67% higher in carriers than in wild-type patients (P = 0.01). The number of patients who achieved serum levels above the therapeutic range (>500 μg/L) was also higher in *22-allele carriers (16.1% vs 2.9%; P = 0.007). CONCLUSION: Being a carrier of the CYP3A4*22 allele increases the serum concentration of quetiapine at comparable doses. Copyright © 2014 by Lippincott Williams & Wilkins.

Bakker M.F.,University Utrecht | Jacobs J.W.G.,University Utrecht | Kruize A.A.,University Utrecht | Van Der Veen M.J.,St Jansdal Hospital | And 5 more authors.
Annals of the Rheumatic Diseases | Year: 2012

Objective: To study whether assessment of rheumatoid arthritis (RA) disease activity in individual patients using the disease activity score in 28 joints (DAS28) or other instruments excluding joints of feet may lead to misclassification of disease activity. Methods: A cohort of RA patients was classified into three 'regional radiographic damage progression' groups: predominantly progression in feet, similar progression in hands and feet and predominantly progression in hands; both in early (0-2 years) and later (2-5 years) disease. Baseline and mean DAS28, individual DAS28 variables and tender joint counts (TJC) and swollen joint counts (SJC) of the feet were compared between groups. The longitudinal relation of DAS28 with radiographic damage was investigated using a mixed model analysis with rheumatoid factor status, baseline joint damage and TJC and SJC of the feet as covariates. Results: Early (n=265) and later (n=200) in the disease course, by definition, the classification procedure resulted in 25% as predominantly foot, 25% as predominantly hand and 50% as similar progressors. In early RA predominantly foot progressors had higher TJC and SJC of the feet compared with predominantly hand progressors (p<0.001), but DAS28 was similar. This was not seen in later disease. The longitudinal relation between DAS28 and radiographic progression was influenced by the region of progression (predominantly foot progressors vs others, p<0.001), suggesting that DAS28 underestimates disease activity in predominantly foot progressors. In this group, joint counts for the feet were independently related to radiographic progression. Conclusions: DAS28 underestimates actual disease activity and expected joint damage of individual early RA patients predominantly with disease in the feet.

Van Der Goes M.C.,University Utrecht | Jacobs J.W.G.,University Utrecht | Jurgens M.S.,University Utrecht | Bakker M.F.,University Utrecht | And 4 more authors.
Osteoporosis International | Year: 2013

Summary: Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early rheumatoid arthritis (RA) patients receiving preventive treatment for osteoporosis. A small increase in lumbar bone mineral density (BMD) during the first year of treatment was recorded, regardless of use of glucocorticoids. Introduction: This study aims to describe effects on BMD of treatment according to EULAR guidelines with a methotrexate-based tight control strategy including 10 mg prednisone daily versus the same strategy without prednisone in early RA patients who received preventive therapy for osteoporosis. Methods: Early RA patients were included in the CAMERA-II trial: a randomized, placebo-controlled, double-blind 2-year trial, in which effects of addition of 10 mg prednisone daily to a methotrexate-based tight control strategy were studied. All patients received calcium, vitamin D and bisphosphonates. Disease activity was assessed every 4 weeks. Radiographs of hands and feet and dual-energy X-ray absorptiometry of lumbar spine and left hip were performed at baseline and after 1 and 2 years of treatment. Results: BMD increased significantly over time in both treatment groups at the lumbar spine with a mean of 2.6 % during the first year (p < 0.001), but not at the hip; at none of the time points did BMD differ significantly between the prednisone and placebo group. Higher age and lower weight at baseline and higher disease activity scores during the trial, but not glucocorticoid therapy, were associated with lower BMD at both the lumbar spine and the hip in mixed-model analyses. Conclusion: Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early RA patients on bisphosphonates. A small increase in lumbar BMD during the first year of treatment was found, regardless of use of glucocorticoids. © 2012 The Author(s).

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