Publications by authors named "Per Wiik Johansen"

11 Publications

  • Page 1 of 1

Useful and necessary about new anticoagulants.

Tidsskr Nor Laegeforen 2016 10 11;136(18):1505. Epub 2016 Oct 11.

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http://dx.doi.org/10.4045/tidsskr.16.0786DOI Listing
October 2016

Warfarin-associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system.

Br J Clin Pharmacol 2011 Feb;71(2):254-62

Department of Pharmacology, Oslo University Hospital, Oslo, Norway.

Aims: To study warfarin associated bleeding events reported to the Norwegian spontaneous reporting system and evaluate the differences in assessment of potentially interacting medicines between reporters and evaluators.

Methods: Data on bleeding events on warfarin were retrieved from the Norwegian spontaneous reporting system database. Key measurements were time to bleeding, use of concomitant medications and the evaluation done by reporters.

Results: In 289 case reports a total of 1261 medicines (median 4.0 per patient, range 1-17) was used. The evaluators (authors of this article) identified 546 medicines including warfarin (median 2.0 per patient, range 1-7) that could possibly cause bleeding alone or in combination. Reporters assessed 349 medicines (median 1.0 per patient, range 1-4) as suspect. Evaluators identified 156 pharmacokinetic and 101 pharmacodynamic interactions, compared with 19 pharmacokinetic and 56 pharmacodynamic interactions reported as suspected by the reporters. Time to bleeding was stated in 224 reports. Among the early bleeding events, the reports on warfarin without interacting medicines showed the highest INR (international normalized ratio). Heparin was used in 17/21 reported bleeding events during the first week on warfarin. Among the late bleeding events, reports with pharmacokinetic interacting medicines had the highest INR.

Conclusions: Concomitant use of potentially interacting medicines was involved in the majority of the warfarin-associated bleeding events reported to the Norwegian spontaneous reporting system. Reporters assessed mostly warfarin as the only contributor to bleeding. In particular, pharmacokinetically interacting medicines were not suspected as contributing to bleeding.
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http://dx.doi.org/10.1111/j.1365-2125.2010.03827.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3040547PMC
February 2011

Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction.

Thromb J 2008 Jun 17;6. Epub 2008 Jun 17.

R&D, Department of Clinical Chemistry, Ulleval University Hospital, Kirkeveien 166, O407 Oslo, Norway.

Background: Warfarin treatment has a narrow therapeutic range, requiring meticulous monitoring and dosage titration. Individual dosage requirement has recently partly been explained by genetic variation of the warfarin metabolizing enzyme CYP2C9 and the Vitamin K-activating enzyme VKORC1. In the WARIS-II study, comparing three different antithrombotic regimens after myocardial infarction, warfarin treatment reduced thrombotic events, but was associated with more frequent bleeding than use of acetylsalisylic acid (ASA) alone.

Aims: The primary aim of the present study was to investigate the relation between genotypes of CYP2C9 and VKORC1 and warfarin maintenance dose in myocardial infarction. The secondary aim was to relate the genotypes to international normalized ratio (INR).

Methods: Genotyping was performed in 212 myocardial infarction patients from the WARIS-II study by robotic isolation of DNA from EDTA whole blood (MagNa Pure LC) before PCR amplification (LightCycler) and melting point analysis.

Results: The 420 C>T substitution of CYP2C9*2, the 1075 A>C substitution of CYP2C9*3 and the 1173 C>T substitution of VKORC1 had minor allele frequencies of, 11.3%, 5.7% and 36.6% respectively. Warfarin weekly dose varied between 17 mg and 74 mg among the patients. INR did not vary between genotypes. Warfarin dosage requirement was significantly associated with CYP2C9 and VKORC1 genotypes, treatment group and age. The VKORC1 genotype contributed 24.5% to the interindividual variation in warfarin dosage, whereas the combined CYP2C9 genotypes were only responsible for 7.2% of the dose variation.

Conclusion: CYP2C9 and VKORC1 genotype frequencies in myocardial infarction patients appear similar to other patient groups and have similar impact on warfarin maintenance dose.
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http://dx.doi.org/10.1186/1477-9560-6-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440373PMC
June 2008

Pharmacokinetics of perfluorobutane following intravenous bolus injection and continuous infusion of sonazoid in healthy volunteers and in patients with reduced pulmonary diffusing capacity.

Ultrasound Med Biol 2008 Mar 21;34(3):494-501. Epub 2007 Dec 21.

Research and Development, GE Healthcare, Oslo, Norway.

The ultrasound contrast agent Sonazoidtrade mark was administered as an i.v. bolus injection of 0.6 microL microbubbles/kg body weight or as a continuous infusion over 30 min at a rate of 1.2 microL microbubbles/kg body weight to healthy volunteers and patients with reduced pulmonary diffusing capacity. Expired air and blood samples were collected from 32 subjects and perfluorobutane (PFB) gas was analyzed using validated gas chromatography mass spectrometry methods. Blood concentrations of PFB declined biphasicly with a distribution half-life (t(0.5 to 15)) of 2 to 3 min and an elimination half-life (t(15 to 120)) of 30 to 45 min. Area under the curve (AUC) values in patients with impaired gas diffusion were significantly larger than those in healthy volunteers. The exhalation kinetics were somewhat variable with a PFB elimination half-life (t(15 to 120)) of 28 to 111 min. Clearance of PFB was independent of study population and mode of administration. There were no deaths and no serious adverse events that resulted in the withdrawal of a subject from the study. With the exception that arthralgia predominated in healthy volunteers, healthy volunteers and diseased subjects did not show a different adverse event profile whether Sonazoid was administered as a bolus injection or as an infusion. Assessment of laboratory parameters (serum biochemistry, haematology and urinalysis), vital signs, oxygen saturation and electrocardiograms (ECGs) showed no changes which caused safety concern. (E-mail: [email protected]).
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http://dx.doi.org/10.1016/j.ultrasmedbio.2007.09.019DOI Listing
March 2008

Thyrotrophin-releasing hormone receptor 1 and prothyrotrophin-releasing hormone mRNA expression in the central nervous system are regulated by suckling in lactating rats.

Eur J Endocrinol 2005 May;152(5):791-803

Institute of Basic Medical Science, Department of Biochemistry, University of Oslo, PO Box 1112 Blindern, N-0317 Oslo, Norway.

Background: The accepted function of the hypothalamic peptide, thyrotrophin-releasing hormone (TRH), is to initiate release of thyrotrophin (TSH) from the pituitary. A physiological role for TRH in lactating rats has not yet been established.

Methods: Tissues were prepared from random-cycling and lactating rats and analysed using Northern blot, real time RT-PCR and quantitative in situ hybridisation.

Results: This study demonstrates that TRH receptor 1 (TRHR1) mRNA expression is up-regulated in the pituitary and in discrete nuclei of the hypothalamus in lactating rats, while proTRH mRNA expression levels are increased only in the hypothalamus. The results were corroborated by quantitative in situ analysis of proTRH and TRHR1. Bromocriptine, which reduced prolactin (PRL) concentrations in plasma of lactating and nursing rats, also counteracted the suckling-induced increase in TRHR1 mRNA expression in the hypothalamus, but had an opposite effect in the pituitary. These changes were confined to the hypothalamus and the amygdala in the brain.

Conclusions: The present study shows that the mechanisms of suckling-induced lactation involve region-specific regulation of TRHR1 and proTRH mRNAs in the central nervous system notably at the hypothalamic level. The results demonstrate that continued suckling is critical to maintain plasma prolactin (PRL) levels as well as proTRH and TRHR1 mRNA expression in the hypothalamus. Increased plasma PRL levels may have a positive modulatory role on the proTRH/TRHR1 system during suckling.
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http://dx.doi.org/10.1530/eje.1.01902DOI Listing
May 2005

[Doping preparations list and exceptions based on medical reasons].

Tidsskr Nor Laegeforen 2005 Jan;125(2):197-8

Stiftelsen Antidoping Norge, Oslo.

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January 2005

[Vitamin K in food and the effect of warfarin].

Tidsskr Nor Laegeforen 2003 Jun;123(13-14):1862-3

Regionalt legemiddelinformasjonssenter (RELIS) Sør, Avdeling for klinisk farmakologi, Rikshospitalet, Oslo.

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June 2003

[Individualized pharmacotherapy based on cytochrome P-450 (CYP) genotyping].

Tidsskr Nor Laegeforen 2002 Nov;122(29):2781-3

Avdeling for klinisk farmakologi, Rikshospitalet 0027 Oslo.

Background: Genetic polymorphisms of the drug-metabolising cytochrome P-450 (CYP) enzymes CYP2C9, CYP2C19 and CYP2D6 have been characterized, and several of these variants lead to reduced or absent activity. This is of clinical importance mainly in patients having two non-functional alleles, phenotypically characterised as "poor metabolisers" (1-10% of Caucasians). Since most drugs are transformed into inactive or less active metabolites, "poor metabolisers" are at increased risk of developing drug induced adverse reactions.

Material And Methods: Studies of relevant literature (MedLine search) in addition to our own experiences, show that CYP genotyping can predict the phenotype and thereby explain some abnormal drug responses and may be used to individualize pharmacotherapy.

Results: At present, CYP genotyping (CYP2C9/2C19/2D6) is most frequently requested in psychiatry and anticoagulant therapy, but the field is expanding. Important factors for implementation of pharmacogenetic methods are accuracy of diagnosis, quality of reports, response time, and cost.

Interpretation: Pharmacogenetic analyses will significantly contribute to reducing treatment costs for drug-induced adverse reactions and costs of sick leave, by predicting the best drug and the most effective and safest dosage. The expenses of full genotyping (CYP2C9/2C19/2D6) are equivalent to one day of sick leave. One might ask: Are pharmacogenetic analyses coming to the point where they drive down costs incurred by illness?
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November 2002

Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype.

Clin Pharmacol Ther 2002 Sep;72(3):333-42

Department of Pharmacology and Pharmaceutical Analysis, School of Pharmacy, University of Oslo, Norway.

Objectives: Recently, it was shown in vitro that the polymorphic enzyme cytochrome P450 (CYP) 2D6 mediates O-demethylation of diltiazem. The aim of this study was to compare the pharmacokinetics of diltiazem and its major metabolites in healthy human volunteers representing different CYP2D6 genotypes.

Methods: Norwegians of Caucasian origin were screened for their CYP2D6 genotype on the LightCycler (Roche Diagnostics, Mannheim, Germany) by melting-curve analysis of allele-specific fluorescence resonance energy transfer probes hybridized to polymerase chain reaction-amplified deoxyribonucleic acid. The first 5 individuals identified with genotypes corresponding to a homozygous extensive, heterozygous extensive, or homozygous poor CYP2D6-metabolizing phenotype, respectively, were voluntarily enrolled in the pharmacokinetic study. The participants received diltiazem, 120 mg, as a single oral dose, and plasma samples were collected up to 24 hours after administration. Plasma samples were purified by solid phase extraction. Diltiazem and 7 phase I metabolites were analyzed by liquid chromatography-mass spectrometry.

Results: The pharmacokinetics of diltiazem was not significantly different between the subgroups. However, the systemic exposure of the pharmacologically active metabolites desacetyl diltiazem and N-demethyldesacetyl diltiazem was > or = 5 times higher in poor CYP2D6 metabolizers than in extensive CYP2D6 metabolizers (P <.01).

Conclusions: CYP2D6 activity does not have a major impact on the disposition of diltiazem. In contrast, desacetyl diltiazem and N-demethyldesacetyl diltiazem are markedly accumulated in individuals expressing a deficient CYP2D6 phenotype. Because these metabolites exhibit pharmacologic properties of possible importance, individual CYP2D6 activity might be an aspect to consider in the clinical use of diltiazem.
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http://dx.doi.org/10.1067/mcp.2002.127396DOI Listing
September 2002