Richard Fux

Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study.

Our objective was to study the impact of the cytochrome P450 (CYP) 2D6 polymorphism on the tolerability of metoprolol in a real‐life primary care setting. The adverse effects studied comprised effects related to the central nervous system, cardiovascular effects, and sexual dysfunction.

Dose‐Proportional Intraindividual Single‐ and Repeated‐Dose Pharmacokinetics of Roflumilast, an Oral, Once‐Daily Phosphodiesterase 4 Inhibitor

The dose‐proportional, intraindividual, single‐ and repeated‐dose pharmacokinetics of roflumilast, an oral, once‐daily phosphodiesterase 4 inhibitor under investigation for chronic obstructive pulmonary disease and asthma, was investigated in healthy subjects. In an open, randomized, 2‐period, 2‐sequence crossover study, 15 subjects received immediate‐release tablets of roflumilast 250 or 500 μg as single (day 1) and as repeated, once‐daily doses for 8 days (days 5–12). Dose‐adjusted point estimates and 90% confidence intervals of test (500 μg)/reference (250 μg) ratios for AUC and Cmax of roflumilast and its pharmacologically active N‐oxide metabolite after single and repeated dosing were all within the standard equivalence acceptance range (0.80, 1.25) indicating dose proportionality. The pharmacokinetic properties of both roflumilast dosage forms provide clinically relevant evidence of predictable, intraindividual total (AUC) and maximum (Cmax) exposure of roflumilast and roflumilast N‐oxide. Repeated oral dosing with roflumilast 250 and 500 μg once daily was well tolerated.

Prediction of breast cancer by profiling of urinary RNA metabolites using Support Vector Machine-based feature selection

BackgroundBreast cancer belongs to the most frequent and severe cancer types in human. Since excretion of modified nucleosides from increased RNA metabolism has been proposed as a potential target in pathogenesis of breast cancer, the aim of the present study was to elucidate the predictability of breast cancer by means of urinary excreted nucleosides.MethodsWe analyzed urine samples from 85 breast cancer women and respective healthy controls to assess the metabolic profiles of nucleosides by a comprehensive bioinformatic approach. All included nucleosides/ribosylated metabolites were isolated by cis-diol specific affinity chromatography and measured with liquid chromatography ion trap mass spectrometry (LC-ITMS). A valid set of urinary metabolites was selected by exclusion of all candidates with poor linearity and/or reproducibility in the analytical setting. The bioinformatic tool of Oscillating Search Algorithm for Feature Selection (OSAF) was applied to iteratively improve features for training of Support Vector Machines (SVM) to better predict breast cancer.ResultsAfter identification of 51 nucleosides/ribosylated metabolites in the urine of breast cancer women and/or controls by LC- ITMS coupling, a valid set of 35 candidates was selected for subsequent computational analyses. OSAF resulted in 44 pairwise ratios of metabolite features by iterative optimization. Based on this approach ultimately estimates for sensitivity and specificity of 83.5% and 90.6% were obtained for best prediction of breast cancer. The classification performance was dominated by metabolite pairs with SAH which highlights its importance for RNA methylation in cancer pathogenesis.ConclusionExtensive RNA-pathway analysis based on mass spectrometric analysis of metabolites and subsequent bioinformatic feature selection allowed for the identification of significant metabolic features related to breast cancer pathogenesis. The combination of mass spectrometric analysis and subsequent SVM-based feature selection represents a promising tool for the development of a non-invasive prediction system.

Cyclooxygenase-2 Expression in Human Colorectal Cancer Is Unrelated to Overall Patient Survival

Purpose: Cyclooxygenase-2 (COX-2) expression in human colorectal cancer and adenoma tissue seems to be higher than in normal mucosa. However, data about the relation between COX-2 expression and patient survival are inconclusive as yet. Therefore, we studied COX-2 expression in surgery tissue and survival time in a cohort of 747 colorectal cancer patients. Experimental Design: Surgical specimens of primary colorectal cancer from 747 individuals were immunostained for COX-2 and evaluated under a transmission light microscope. COX-2 expression was scored according to intensity and extent of staining, resulting in the COX-2 immunoreactivity score (IRS-COX2). All possible cutoff points for IRS-COX2 were analyzed for a relation between COX-2 expression and patient survival. Results: Both univariable and multivariable analysis have shown that the COX-2 expression in human tumor epithelial cells was unrelated to overall patient survival and to disease-free survival, irrespectively of the cutoff point for IRS-COX2. The survival rates for 1, 3, 5, and 10 years were 81.0%, 66.8%, 60.2%, and 49.8% (median: 117.3 months; 95% confidence interval, 102.3-132.0), respectively. In the multivariable analysis, only node and metastasis were significantly related to overall patient survival. Similar results were obtained when stage IV and rectal cancer patients were excluded from the analysis. Conclusions: COX-2 expression in tumor epithelial cells does not seem to be related to survival of colorectal cancer patients. Besides COX-2, there are several targets, such as the peroxisome proliferator–activated receptors, that are involved in carcinogenesis and may be modulated by nonsteroidal anti-inflammatory drugs. Further studies are needed to determine their prognostic relevance.

Identification of Urinary Modified Nucleosides and Ribosylated Metabolites in Humans Via Combined ESI-FTICR MS and ESI-IT MS Analysis

The physiological response of the human body to several diseases can be reflected by the metabolite pattern in biological fluids. Cancer, like other diseases accompanied by metabolic disorders, causes characteristic effects on cell turnover rate, activity of modifying enzymes, and RNA/DNA modifications. This results in an altered excretion of modified nucleosides and biochemically related compounds. In the course of our metabolic profiling project, we screened 24-h urine of patients suffering from lung, rectal, or head and neck cancer for previously unknown ribosylated metabolites. Therefore, we developed a sample preparation procedure based on boronate affinity chromatography followed by additional prepurification with preparative TLC. The isolated metabolites were analyzed by ion trap mass spectrometry (IT MS) and Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS). IT MS was applied for LC-auto MS3 screening runs and MSn(n=4–6) syringe pump infusion experiments, yielding characteristic fragmentation patterns. FTICR MS measurements enabled the calculation of corresponding molecular formulae based on accurate mass determination (mass accuracy: 1–5 ppm for external and sub-ppm values for internal calibration). We were able to identify 22 metabolites deriving from cellular RNA metabolism and related metabolic pathways like histidine metabolism, purine biosynthesis, methionine/polyamine cycle, and nicotinate/nicotinamide metabolism. The compounds 1-ribosyl-3-hydroxypyridinium, 1-ribosyl-pyridinium, and 3-ribosyl-1-methyl-l-histidinium as well as a series of ribosylated histamines, conjugated to carboxylic acids at the Nω-position were found as novel urinary constituents. The occurrence of the modified nucleosides 2-methylthio-N6-(cis-hydroxyisopentenyl)-adenosine, 5-methoxycarbonylmethyl-2-thiouridine, N6-methyl-N6-threonylcarbamoyladenosine, and 2-methylthio-N6-threonylcarbamoyladenosine in human urine is verified for the first time.

Ginger-Associated Overanticoagulation by Phenprocoumon

OBJECTIVE To report a case of ginger–phenprocoumon interaction resulting in an elevated international normalized ratio (INR) and epistaxis. CASE SUMMARY A 76-year-old white European woman on long-term phenprocoumon therapy with an INR within the therapeutic range began using ginger products. Several weeks later, she developed an elevated INR up to 10 and epistaxis. The INR returned to the normal range after ginger was stopped and vitamin K1 was given. DISCUSSION There have been a number of investigations resulting in conflicting opinions on the effect of ginger on hemostasis, specifically, platelet inhibition. Nevertheless, based on these investigations, recommendations have been issued to refrain from ingesting ginger and other herbals like garlic or ginkgo biloba in situations where bleeding may be critical. An objective causality assessment revealed that the adverse drug event as a result of the phenprocoumon and ginger interaction was probable. CONCLUSIONS As of writing, this was the first case report that may support an interaction between an oral anticoagulant and ginger together with a brief review of the literature on ginger and hemostasis. As this interaction was observed only by chance, this case highlights the importance of self-control of anticoagulation with coumarins particularly for the detection of unknown interactions.

Effect of High‐Dose Metronidazole on Pharmacokinetics of Oral Budesonide and Vice Versa: A Double Drug Interaction Study

Recent case reports suggest that addition of high‐dose metronidazole might be associated with elevated plasma concentrations of substrates of cytochrome P450 (CYP) 3A. Because patients with fistulizing Crohns disease benefit by using high doses of metronidazole for prolonged periods, this studys primary aim was to evaluate the effect of high‐dose metronidazole on the pharmacokinetics of oral budesonide, a sensitive substrate of CYP3A commonly prescribed in acute inflammatory bowel disease. Twelve healthy adults received 1.5 g metronidazole per day over 1 week. The CYP3A‐dependent metabolic profile of an oral dose of budesonide (3 mg) and that of endogenous cortisol were compared intraindividually before and after administration of metronidazole. There was neither a significant effect of high‐dose metronidazole on the area under the plasma concentration‐time curve (AUC) of budesonide (90% confidence interval, 79%–115%) nor on the AUC ratios of 6β‐hydroxybudesonide/budesonide and 16α‐hydroxyprednisolone/budesonide. In parallel, metronidazole did not significantly alter formation of 6β‐hydroxycortisol. Vice versa, budesonide did not affect the AUC of metronidazole (90% confidence interval, 91%–100%). The authors conclude that in contrast to concomitant intake of other imidazoles such as ketoconazole, concomitant intake of metronidazole may not lead to serious safety concerns due to elevated systemic concentrations of the glucocorticoid budesonide.

Anaphylaxis to intravenous sinistrin

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