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Biomedical subjects

Henk-Jan Guchelaar

Publications and source records attributed to Henk-Jan Guchelaar.

At least 19 recordsLinked to original sources
PubMed2007

Influence of initial use of serotonergic antidepressants on antiparkinsonian drug use in levodopa-using patients.

OBJECTIVE: To assess whether there is an association between initial use of serotonergic antidepressants and changes in antiparkinsonian drug treatment. METHODS: A retrospective cohort study was performed with the PHARMO record linkage system. All patients from 1994 until 2004 of 40 years or older who were first time users of an antidepressant and who had used a levodopa-containing drug at least 180 days before initiation of the antidepressant were included. The maximum follow-up time was 180 days. The first change in antiparkinsonian drug treatment, defined as an increase in the daily dosage of any antiparkinsonian drug, the start of a new antiparkinsonian drug or a change in the dosage form during the follow-up period, was taken as an endpoint. Antidepressants were classified in two ways: according to their class [selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA) or other antidepressants] or by the extent of their inhibition of serotonin reuptake (high, intermediate or low). RESULTS: A total of 221 patients was included in our study. The adjusted hazard ratio for a change in antiparkinsonian drug treatment was 0.7 (95% CI 0.3-1.5) comparing SSRI with TCA users, and it was 0.9 (95% CI 0.4-2.1) comparing users of other antidepressants with TCA users. The adjusted hazard ratio for a change in antiparkinsonian drug treatment was 0.6 (95% CI 0.3-1.4) comparing users of antidepressants with high versus low extent of inhibition of serotonin reuptake, and it was 0.7 (95% CI 0.3-1.4) comparing users of antidepressants with intermediate versus low extent of inhibition of serotonin reuptake. CONCLUSION: Based on these observations, we found no evidence to be more cautious using SSRIs or serotonergic antidepressants compared to other antidepressants in patients with Parkinson's disease.

Aged↗
PubMed2006

Increased dihydropyrimidine dehydrogenase activity associated with mild toxicity in patients treated with 5-fluorouracil and leucovorin.

Dihydropyrimidine dehydrogenase (DPD) plays a pivotal role in the metabolism of 5FU. The prognostic significance of DPD activity in peripheral blood mononuclear (PBM) cells and buccal mucosa cells with respect to toxicity was investigated in 44 patients treated with 5FU-leucovorin. Grade III/IV haematological and grade III/IV gastrointestinal toxicity were observed in 25% and 21% of the patients, respectively. No association was observed between the DPD activity in buccal mucosa cells and toxicity. In contrast, the mean DPD activity in PBM cells proved to be increased in patients experiencing grade I/II neutropenia when compared to patients without neutropenia and those suffering from grade III/IV neutropenia (P=0.002). Patients with a high-normal DPD activity proved to be at risk of developing mild toxicity upon treatment with 5FU-leucovorin, suggesting an important role of DPD in the aetiology of toxicity associated with catabolites of 5FU.

Adult↗
PubMed2006

Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes.

OBJECTIVE: To determine associations of methotrexate (MTX) efficacy and toxicity with single-nucleotide polymorphisms (SNPs) in genes coding for folate pathway enzymes in patients with early rheumatoid arthritis (RA). METHODS: Patients (n=205) with active RA received MTX at an initial dosage of 7.5 mg/week, which was increased to 15 mg/week and combined with folic acid (1 mg/day) after 4 weeks. If the Disease Activity Score in 44 joints (DAS44) was >2.4 at 3 months, MTX was increased to 25 mg/week. MTX efficacy was evaluated at 3 and 6 months and compared for genotypes in 3 analyses: patients with and without good response (DAS44 1.2), and patients with and without moderate improvement (DeltaDAS44>0.6). The association between MTX-related adverse drug events (ADEs) and genotype was evaluated by comparing genotypes between patients with and without ADEs, specifically pneumonitis, gastrointestinal ADEs, skin and mucosal ADEs, and elevated liver enzyme levels. The following SNPs were analyzed: methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, dihydrofolate reductase (DHFR) -473G>A, DHFR 35289G>A, and reduced folate carrier 80G>A. In case of significant differences, odds ratios (ORs) were calculated. RESULTS: At 6 months, MTHFR 1298AA was associated with good improvement relative to 1298C (OR 2.3, 95% confidence interval [95% CI] 1.18-4.41), which increased with increased copies of the MTHFR 677CC haplotype. In contrast, MTHFR 1298C allele carriers developed more ADEs (OR 2.5, 95% CI 1.32-4.72). CONCLUSION: Patients with MTHFR 1298AA and MTHFR 677CC showed greater clinical improvement with MTX, whereas only the MTHFR 1298C allele was associated with toxicity. In the future, MTHFR genotypes may help determine which patients will benefit most from MTX treatment.

Antirheumatic Agents↗
PubMed2006

Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis.

OBJECTIVE: Among patients with rheumatoid arthritis (RA), there is a high degree of interindividual variability in the degree of response to methotrexate (MTX) treatment. This study was undertaken to explore polymorphisms in genes contributing to antiinflammatory adenosine release as novel predictors of MTX treatment outcome. METHODS: In 205 patients with newly diagnosed RA, 5 polymorphisms in 5 genes coding for enzymes related to the release of adenosine were analyzed. All patients received standardized MTX treatment (up to 25 mg per week orally), combined with folic acid. MTX efficacy was evaluated by the Disease Activity Score (DAS) and compared among genotypes. The association between MTX-related adverse events and genotype was also assessed. The following polymorphisms were determined: AMPD1 34C>T, ATIC 347C>G, ITPA 94C>A, MTR 2756A>G, and MTRR 66A>G. When significant differences were found by chi-square analysis, odds ratios (ORs) and 95% confidence intervals were calculated. RESULTS: Patients carrying the AMPD1 34T allele, ATIC 347CC, or ITPA 94CC were more likely to have a good clinical response, as defined by a DAS of < or =2.4 (OR [95% confidence interval] 2.1 [1.0-4.5], 2.5 [1.3-4.7], and 2.7 [1.1-8.1], respectively). The likelihood of a good clinical response was increased if patients possessed all 3 favorable genotypes (OR 27.8 [95% confidence interval 3.2-250]). Regarding toxicity, only ATIC G allele carriers experienced a greater frequency of adverse events (OR 2.0 [95% confidence interval 1.1-3.7]). CONCLUSION: Polymorphisms in the AMPD1, ATIC, and ITPA genes are associated with good clinical response to MTX treatment. These findings indicate that genotyping may help in the identification of patients who will benefit most from MTX treatment and may assist clinicians in making treatment decisions regarding patients with recent-onset RA.

AMP Deaminase↗
PubMed2006

Genetic markers of treatment response in rheumatoid arthritis.

Rheumatoid arthritis patients exhibit a considerable interindividual variability in response to drug treatment. Although many disease-related and demographic factors have been studied to predict treatment outcome, the effective disease-modifying antirheumatic drug (DMARD) therapy is not yet allocated based on factors that predict efficacy. Individual genetic characteristics are thought to play an important role in treatment response; therefore, current research aims to identify these genetic predictors for clinical response. Pharmacogenetic studies are beginning to provide results, which suggests that personalized treatment maximization of DMARD efficacy and minimization of adverse drug reactions are feasible.

Antirheumatic Agents↗
PubMed2006

Formulation, quality control and shelf life of the experimental cytostatic drug cyclopentenyl cytosine.

This paper describes the formulation and quality control of an aqueous sterilized formulation of the experimental cytostatic drug cyclopentenyl cytosine (CPEC) to be used in Phase I/II clinical trials. The raw drug substance was extensively tested. A High Pressure Liquid Chromotography (HPLC) method was validated for the quality control of the formulated product. The aqueous formulation was found to be stable for at least 2 years at 2-8 degrees C. Sterilization (15 min at 121 degrees C) showed no influence on drug stability. The results show that CPEC can be formulated in an aqueous solution. The described HPLC method is a useful tool in the pharmaceutical quality control.

Antineoplastic Agents↗
PubMed2006

Once-daily intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics and early clinical outcomes.

We studied the pharmacokinetics and clinical outcome of a new once-daily intravenous area under the curve-targeted dosing scheme for busulfan based on body surface area. Eighteen children undergoing busulfan-based conditioning for allogeneic stem cell transplantation were enrolled. The age of the children ranged from 0.5 to 16 years. For all children, the starting dose was 80 mg/m. Unlimited dose adjustment was allowed to reach the target area under the curve (3800 micromol/l . min). This target area under the curve was determined on the basis of a previous study in our hospital. Pharmacokinetic studies were performed after the first dose. The median area under the curve on day 1 was 2616 (range 1781-5040) micromol/l . min at a dose of 80 mg/m. This resulted in a median dose increment to 114 (range 62-168) mg/m to reach the target area under the curve. In only one patient, the dose was decreased. Donor engraftment was established in 14 out of 18 patients (78%). Two of the four patients were successfully retransplanted. Relapse occurred in two patients (one died, one received additional treatment). Fourteen patients survived with a median follow-up of 1.6 years (1.0-2.2 years). The disease-free survival was 66% (12 of 18 patients). Despite the high systemic peak levels, there was no new unexpected or unusual toxicity. Moderate veno-occlusive disease was seen in one patient only. We conclude that intravenous busulfan in children administered once daily is safe, convenient and feasible, and can be dosed surface-based, independent of age. There was very limited (liver) toxicity, but the rejection rate was relative high, which can be probably overcome by a higher exposure to busulfan. Future investigations should be aimed at further optimizing the target area under the curve of intravenous busulfan for specific patient groups.

Adolescent↗
PubMed2006

Multiplex pyrosequencing of two polymorphisms in DNA repair gene XRCC1.

DNA repair enzymes play a pivotal role in platinum-based chemotherapy. Within the gene encoding for the base excision repair enzyme XRCC1, several nonsynonymous polymorphisms have been identified. It has been shown that the Arg399Gln single-nucleotide polymorphism results in a polymorphic enzyme that is less capable of initiating DNA repair. We developed a multiplex pyrosequence assay to simultaneously detect two nonsynonymous polymorphisms within the XRCC1 gene. Both of these polymorphisms resulted in amino acid changes: G/A in codon 399 changes Arg into Gln, and deletion of A in the second position of codon 576 results in a stopcodon. We established the frequency of these mutations in 270 patients suffering from colorectal cancer. Allele frequencies of G in second position of codon 399 and A in the second position codon 576 are 61.1 and 99.6%, respectively, in these patients. This fast and reliable method allows for simultaneous detection of the infrequent mutant C or CT alleles instead of the A deletion at codon 576. The method may be used in pharmacogenetic studies of platinum-based chemotherapy.

Colorectal Neoplasms↗
PubMed2005

Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan.

PURPOSE: Milk thistle (Silybum marianum) is one of the most commonly used herbal therapies, and its principal constituent silybin significantly inhibits cytochrome P450 isoform 3A4 (CYP3A4) and UDP glucuronosyltransferase isoform 1A1 (UGT1A1) in vitro. Here, we investigated whether milk thistle affects the pharmacokinetics of irinotecan, a substrate for CYP3A4 and UGT1A1, in humans. EXPERIMENTAL DESIGN: Six cancer patients were treated with irinotecan (dose, 125 mg/m(2)) given as a 90-minute infusion once every week. Four days before the second dose, patients received 200 mg milk thistle, thrice a day, for 14 consecutive days. Pharmacokinetic studies of irinotecan and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38), 7-ethyl-10-[3,4,5-trihydroxy-pyran-2-carboxylic acid]-camptothecin (SN-38-glucuronide), and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin were done during the first three irinotecan administrations. RESULTS: Short-term (4 days) or more prolonged intake of milk thistle (12 days) had no significant effect on irinotecan clearance (mean, 31.2 versus 25.4 versus 25.6 L/h; P = 0.16). The area under the curve ratio of SN-38 and irinotecan was slightly decreased by milk thistle (2.58% versus 2.23% versus 2.17%; P = 0.047), whereas the relative extent of glucuronidation of SN-38 was similar (10.8 versus 13.5 versus 13.1; P = 0.64). Likewise, the area under the curve ratio of 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin and irinotecan was unaffected by milk thistle (0.332 versus 0.285 versus 0.337; P = 0.53). The maximum plasma concentrations of silybin ranged between 0.0249 and 0.257 micromol/L. CONCLUSIONS: Silybin concentrations after intake of milk thistle are too low to significantly affect the function of CYP3A4 and UGT1A1 in vivo, indicating that milk thistle is unlikely to alter the disposition of anticancer drugs metabolized by these enzymes.

Adolescent↗
PubMed2005

Absence of cardiotoxicity of the experimental cytotoxic drug cyclopentenyl cytosine (CPEC) in rats.

The experimental anticancer drug cyclopentenyl cytosine (CPEC) was associated with cardiotoxicity in a phase I study. The aim of the present study was twofold; first we investigated whether the observed effects could be reproduced in in-vitro and in-vivo rat models. Second, we intended to investigate the underlying mechanism of the possible cardiotoxicity of CPEC. Effects on frequency and contractility were studied on the isolated atria of 18 male Wistar rats. Atria were incubated with 0.1 mmol L(-1) (n = 6) or 1 mmol L(-1) (n = 6) CPEC for 1.5 h and compared with control atria (incubation with buffer solution, n = 6). The cardiac apoptosis-inducing potential was studied in-vivo on 66 rats by 99mTc-Annexin V scintigraphy, followed by postmortem determination of radioactivity in tissues, histological confirmation with the TUNEL assay (late-phase apoptosis), and immunohistochemical staining for cleaved caspase 3 and cytochrome C (early-phase apoptosis). Serum levels of the necrotic cardiomyopathy marker troponin T were also determined. No effect on heart frequency was found in the isolated atria after CPEC treatment. A trend towards a decrease of contraction force was observed. However, the differences were not statistically significant. 99mTc-Annexin V scintigraphy showed no increase in cardiac uptake ratio upon CPEC treatment in the in-vivo rat model, which was confirmed by determination of radioactivity in heart versus blood ratios. At each section a few individual isolated late apoptotic cells (< 5) could be identified by the TUNEL assay in the highest CPEC dose group (90 mg kg(-1)) but not in controls or in rats treated with 60 mg kg(-1) CPEC. Staining for the early apoptosis markers cleaved caspase 3 and cytochrome C did not reveal any significant differences between treated and control rats. Cardiac troponin T levels were not increased after CPEC treatment. CPEC does not affect heart frequency or contraction force in our cardiotoxicity models. Moreover, we did not find an indication of CPEC-induced apoptosis in heart tissue.

Animals↗
PubMed2005

Medication errors: hospital pharmacist perspective.

In recent years medication error has justly received considerable attention, as it causes substantial mortality, morbidity and additional healthcare costs. Risk assessment models, adapted from commercial aviation and the oil and gas industries, are currently being developed for use in clinical pharmacy. The hospital pharmacist is best placed to oversee the quality of the entire drug distribution chain, from prescribing, drug choice, dispensing and preparation to the administration of drugs, and can fulfil a vital role in improving medication safety. Most elements of the drug distribution chain can be optimised; however, because comparative intervention studies are scarce, there is little scientific evidence available demonstrating improvements in medication safety through such interventions. Possible interventions aimed at reducing medication errors, such as developing methods for detection of patients with increased risk of adverse drug events, performing risk assessment in clinical pharmacy and optimising the drug distribution chain are discussed. Moreover, the specific role of the clinical pharmacist in improving medication safety is highlighted, both at an organisational level and in individual patient care.

Humans↗
PubMed2004

The risk of cancer in users of statins.

PURPOSE: Several preclinical studies suggested a role for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the treatment of cancer. The objective of this study was to compare the risk of incident cancer between users of statins and users of other cardiovascular medication. METHODS: Data were used from the PHARMO database, containing drug dispensing records from community pharmacies and linked hospital discharge records for residents of eight Dutch cities. The study base included all patients with one or more prescriptions for cardiovascular drugs in the period between January 1, 1985 and December 31, 1998. Cases were identified as patients in the study base with a diagnosis of incident cancer and matched with four to six controls on sex, year of birth, geographic region, duration of follow-up, and index date. The analysis was adjusted for diabetes mellitus; prior hospitalizations; comorbidity; and use of diuretics, angiotensin-converting enzyme inhibitors, calcium-channel blockers, nonsteroidal anti-inflammatory drugs, sex hormones, and other lipid-lowering drug therapies. RESULTS: In the study base, 3129 patients were identified and matched to 16976 controls. Statin use was associated with a risk reduction of cancer of 20% (adjusted odds ratio [OR], 0.80; 95% CI, 0.66 to 0.96). Our data suggest that statins are protective when used longer than 4 years (adjusted OR, 0.64; 95% CI, 0.44 to 0.93) or when more than 1350 defined daily doses are taken (adjusted OR, 0.60; 95% CI, 0.40 to 0.91). CONCLUSION: This observational study suggests that statins may have a protective effect against cancer.

Aged↗
PubMed2004

Cardiotoxicity of cytotoxic drugs.

Cardiotoxicity is a well-known side effect of several cytotoxic drugs, especially of the anthracyclines and can lead to long term morbidity. The mechanism of anthracycline induced cardiotoxicity seems to involve the formation of free radicals leading to oxidative stress. This may cause apoptosis of cardiac cells or immunologic reactions. However, alternative mechanisms may play a role in anthracycline induced cardiotoxicity. Cardiac protection can be achieved by limitation of the cumulative dose. Furthermore, addition of the antioxidant and iron chelator dexrazoxane to anthracycline therapy has shown to be effective in lowering the incidence of anthracycline induced cardiotoxicity. Other cytotoxic drugs such as 5-fluorouracil, cyclophosphamide and the taxoids are associated with cardiotoxicity as well, although little is known about the possible mechanisms. Recently, it appeared that some novel cytotoxic drugs such as trastuzumab and cyclopentenyl cytosine also show cardiotoxic side effects.

Anthracyclines↗
PubMed2004

Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer.

Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors - HMG-CoA reductase inhibitors) have been approved for the treatment of lipid disorders. Recently, in vivo studies with experimental animals and in vitro studies indicated a possible role for statins in the treatment of malignancies. Inhibition of the enzyme HMG-CoA reductase results in decreased farnesylation and geranylgeranylation of several proteins essential for cellular proliferation and survival. Inhibition of Ras farnesylation was originally thought to be the mechanism that mediates statin-induced effects in cancer. Consequently, specific inhibitors of the enzyme farnesyltransferase (FTIs) were developed. Currently, the mechanisms that mediate statin- and FTI-induced antitumour effects are questioned. It remains unclear which proteins and signal transduction cascades are involved. This review focuses on the effects and possible therapeutic application of statins and FTIs. Antitumour properties such as induction of growth arrest and apoptosis, inhibition of metastasis and inhibition of angiogenesis are discussed. Furthermore, the mechanisms of statin- and farnesyltransferase inhibitor-induced effects and the involvement of a number of cellular components (such as farnesylated and geranylgeranylated proteins, the mitogen-activated protein kinase signalling pathway, the phosphoinositide 3'-kinase signalling pathway, and cell cycle regulatory proteins) are reviewed. In addition, clinical and epidemiological data with respect to statins and farnesyltransferase inhibitors are summarised. We propose that inhibitors of the mevalonate pathway are particularly effective when administered in combination with other drugs. Therefore, the mechanisms and effects of combined therapy of statins or farnesyltransferase inhibitors with chemotherapeutics, biphosphonates, non-steroidal anti-inflammatory drugs, specific inhibitors of geranylgeranyltransferase and inhibitors of tyrosine kinase activity are discussed.

Alkyl and Aryl Transferases↗
PubMed2004

Medication error due to ambiguous labelling of a commercial product.

Medication errors may involve prescribing, dispensing, preparation and administration of drugs. We report a case in which an administration error occurred due to ambiguous labelling of a commercial drug. Tablets were packed in sets of two tablets per blister with the print on the blister 'Zelitrex 500', making the amount of drug per tablet unclear. A short survey among nurses and pharmacy technicians showed that the majority interpreted the strength of the tablets incorrectly. This case shows that, despite regulations for controlling and accepting labelling before marketing, ambiguous labelling may occur and can lead to medication errors.

Acyclovir↗
PubMed2003

Direct access of drugs to the human brain after intranasal drug administration?

It has been suggested that intranasal (IN) drug delivery could be used to administer drugs directly to the brain, bypassing the blood-brain barrier. Conclusive evidence of this proposed route of drug transport has not been observed by IN-IV comparison. In eight neurosurgery patients with a CSF drain, the uptake in CSF and plasma after IN and IV drug administration was compared. No evidence of direct access of the drugs from the nose to the CSF was found.

Administration, Intranasal↗