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Haslemo T.,Center for Psychopharmacology | Refsum H.,Center for Psychopharmacology | Molden E.,Center for Psychopharmacology | Molden E.,University of Oslo
British Journal of Clinical Pharmacology | Year: 2011

AIM To investigate the potential interaction between olanzapine, a CYP1A2 substrate, and ethinylestradiol-containing contraceptives (ECC). METHODS The study was carried out at a routine therapeutic drug monitoring service. To identify patients who were co-administered ECC or other contraceptives, a questionnaire was sent to the physician who ordered serum monitoring of olanzapine for women aged 18-40 years during an 18 month period. The physicians were asked to provide information about contraceptive use and smoking habits. When questionnaires were returned by the physicians, the respective serum concentration data were included in the analysis. Patients were stratified into users of ECC, progestogen-based contraceptives (PBC) or no contraceptives. Dose-adjusted serum concentrations of olanzapine and the metabolite N-desmethyl olanzapine were compared between the subgroups. RESULTS A total of 149 patients were included in the study (10 ECC users and 10 PBC users). In users of ECC, we found no differences in serum concentrations of olanzapine, but significantly lower concentrations of the CYP1A2-mediated metabolite N-desmethyl olanzapine compared with users of PBC (P=0.019) and non-contraceptive users (P=0.012). CONCLUSION The present study confirms that ECC exhibit CYP1A2-inhibitory properties in terms of significantly lower exposure of N-desmethyl olanzapine. However, the inhibition does not provide clinically relevant changes in serum concentrations of olanzapine. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society. Source

Narum S.,Center for Psychopharmacology | Narum S.,University of Oslo | Westergren T.,University of Oslo | Klemp M.,Norwegian Knowledge Center for the Health Services | Klemp M.,University of Oslo
BMJ Open | Year: 2014

Objective: To assess whether corticosteroids are associated with increased risk of gastrointestinal bleeding or perforation. Design: Systematic review and meta-analysis of randomised, double-blind, controlled trials comparing a corticosteroid to placebo for any medical condition or in healthy participants. Studies with steroids given either locally, as a single dose, or in crossover studies were excluded. Data sources: Literature search using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews between 1983 and 22 May 2013. Outcome measure: Outcome measures were the occurrence of gastrointestinal bleeding or perforation. Predefined subgroup analyses were carried out for disease severity, use of non-steroidal anti-inflammatory drugs (NSAIDs) or gastroprotective drugs, and history of peptic ulcer. Results: 159 studies (N=33 253) were included. In total, 804 (2.4%) patients had a gastrointestinal bleeding or perforation (2.9% and 2.0% for corticosteroids and placebo). Corticosteroids increased the risk of gastrointestinal bleeding or perforation by 40% (OR 1.43, 95% CI 1.22 to 1.66). The risk was increased for hospitalised patients (OR 1.42, 95% CI 1.22 to 1.66). For patients in ambulatory care, the increased risk was not statistically significant (OR 1.63, 95% CI 0.42 to 6.34). Only 11 gastrointestinal bleeds or perforations occurred among 8651 patients in ambulatory care (0.13%). Increased risk was still present in subgroup analyses (studies with NSAID use excluded; OR 1.44, 95% CI 1.20 to 1.71, peptic ulcer as an exclusion criterion excluded; OR 1.47, 95% CI 1.21 to 1.78, and use of gastroprotective drugs excluded; OR 1.42, 95% CI 1.21 to 1.67). Conclusions: Corticosteroid use was associated with increased risk of gastrointestinal bleeding and perforation. The increased risk was statistically significant for hospitalised patients only. For patients in ambulatory care, the total occurrence of bleeding or perforation was very low, and the increased risk was not statistically significant. Source

Kersten H.,University of Oslo | Molden E.,University of Oslo | Molden E.,Center for Psychopharmacology | Willumsen T.,University of Oslo | And 2 more authors.
British Journal of Clinical Pharmacology | Year: 2013

Aim: This study evaluated a presumed gradual decline in cognitive function in nursing home residents when the anticholinergic drug scale (ADS) score increased above 3. Method: The study population was recruited from 21 nursing homes in Norway. Criteria for inclusion were ADS score≥3 and no severe dementia, defined as Clinical Dementia Rating (CDR) score < 3. Primary cognitive end points were CERAD 10-word lists for recall and Mini Mental State Examination (MMSE). Secondary end points were activity of daily living (ADL), mouth dryness and serum anticholinergic activity (SAA). The patients were stratified into subgroups according to ADS score, i.e. a reference group with score 3 and test groups with scores 4, 5 or ≥6. End points were compared by analyses of covariance (ancova). Results: Overall, 230 of the 1101 screened nursing home residents (21%) had an ADS score ≥3. After exclusion 101 residents were recruited and among these, 87 managed to participate in the study. No significant differences were detected in cognitive function or ADL when ADS increased above 3 (P > 0.10), but in vivo (mouth dryness) and in vitro (SAA) measures of peripheral anticholinergic activity were significantly higher in patients with an ADS score ≥6 (P < 0.01). Conclusion: The present study does not support a progressive decline in cognitive function with ADS score above 3. This might indicate that the ADS score model has limited potential to predict the clinical risk of central anticholinergic side effects in frail elderly patients receiving multiple anticholinergic drugs. © 2012 The British Pharmacological Society. Source

Hoiseth G.,Norwegian Institute of Public Health | Hoiseth G.,Center for Psychopharmacology | Nordal K.,Norwegian Institute of Public Health | Pettersen E.,Akershus University Hospital | Morland J.,Norwegian Institute of Public Health
Alcoholism: Clinical and Experimental Research | Year: 2012

Background: The aims of this study were to investigate detection times for ethyl glucuronide (EtG) and ethyl sulphate (EtS) in urine samples of patients with decreased kidney function and to compare these with those previously reported for healthy volunteers. Methods: Fourteen patients were included, each delivering 10 urine samples after a nonsupervised intake of 0.1 to 1.4 g ethanol/kg body weight. The urinary detection times of EtG and EtS in these patients were adjusted for doses and compared to previously published healthy volunteers. Results: Detection times were significantly longer in patients with decreased renal function compared with healthy volunteers (p < 0.01 for both EtG and EtS). Conclusions: Even after very minor alcohol intakes, these patients could fail alcohol tests based on the detection of conjugated ethanol metabolites for several days and wrongly be suspected of higher or more recent alcohol intakes than actually have found place. © 2012 by the Research Society on Alcoholism. Source

Jakobsen S.M.,University of Oslo | Kersten H.,University of Oslo | Molden E.,University of Oslo | Molden E.,Center for Psychopharmacology
Journal of the American Geriatrics Society | Year: 2011

OBJECTIVES: To compare the brain anticholinergic activities of five urinary spasmolytic drugs (USDs). DESIGN: In vitro study. SETTING: Laboratory. PARTICIPANTS: None. MEASUREMENTS: A validated 96-well anticholinergic radio receptor bioassay using small incubation volumes (240 μL per well) was applied in the current study. The different USDs (tolterodine, oxybutynin, solifenacin, darifenacin, and 5-hydroxy-methyl-tolterodine (5-HMT; the active metabolite of fesoterodine) were dissolved in plasma in their respective therapeutic concentration ranges. The plasma samples were added directly to the wells of 96 filter plates, wherein the incubation, filtration, and counting of undisplaced radioactivity was performed. Standard curves with atropine were used as reference for estimations of anticholinergic activity (AA). RESULTS: 5-HMT and tolterodine displayed the highest AA of the tested USDs. In the middle of the therapeutic concentration range, the central anticholinergic potency of 5-HMT and tolterodine was more than 10 times as high as that of oxybutynin, solifenacin, and darifenacin. Darifenacin exhibited the lowest AA at therapeutic serum concentrations ( Source

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