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Dahl, Marja-Liisa
Publications (10 of 34) Show all publications
Gokalp, O., Gunes, A., Cam, H., Cure, E., Aydin, O., Tamer, M. N., . . . Dahl, M.-L. (2011). Mild hypoglycaemic attacks induced by sulphonylureas related to CYP2C9, CYP2C19 and CYP2C8 polymorphisms in routine clinical setting. European Journal of Clinical Pharmacology, 67(12), 1223-1229
Open this publication in new window or tab >>Mild hypoglycaemic attacks induced by sulphonylureas related to CYP2C9, CYP2C19 and CYP2C8 polymorphisms in routine clinical setting
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2011 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 67, no 12, p. 1223-1229Article in journal (Refereed) Published
Abstract [en]

To evaluate the impact of polymorphisms in the cytochrome P450 (CYP) 2C9, 2C19 and 2C8 genes on the risk of mild hypoglycaemic attacks in patients treated with sulphonylureas. One hundred and eight type 2 diabetic patients (50 men, 58 women), treated with oral antidiabetics, including at least one from the sulphonylurea group (glimepiride n = 50, gliclazide n = 46, or glipizide n = 12) for 3 months or longer, were included in the study. Symptoms of hypoglycaemia (sweating, tremor, anxiety and palpitations) during a 3 month period were recorded and confirmed by home glucose measurements. Gender, age, body mass index, creatinine clearance, HbA1c, oral antidiabetic dose and concomitant medication were assessed together with functional CYP2C9, CYP2C19 and CYP2C8 polymorphisms, analysed by real-time PCR methods. Fifteen patients (eight men, seven women) reported hypoglycaemia symptoms which were validated by their home glucose measurements (< 70 mg/dl). Heterozygosity and homozygosity for CYP2C9 variant alleles (*2 or *3) tended to be more frequent among patients who reported hypoglycaemic attacks (60 and 7%) than those who did not (39 and 3%). Similarly, the CYP2C8*1/*3 genotype tended to be more frequent in patients with (47%) than without (27%) hypoglycaemia, while no such trend was observed for CYP2C19 variants. However, only in the gliclazide group a significant association between CYP2C9 genotype and hypoglycaemic attacks was observed (P = 0.035). None of the other covariates showed any significant association with the risk of hypoglycaemic attacks. CYP2C9 polymorphisms leading to decreased enzyme activity show a modest impact on the risk of mild hypoglycaemia attacks during oral antidiabetic treatment, with a significant association in patients treated with gliclazide.

Keywords
Sulphonylurea, Hypoglycaemic attacks, CYP2C9, CYP2C19, CYP2C8, Polymorphism, Gliclazide, Glimepiride, Glipizide
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-163639 (URN)10.1007/s00228-011-1078-4 (DOI)000297127000003 ()
Available from: 2011-12-16 Created: 2011-12-13 Last updated: 2017-12-08Bibliographically approved
Lindh, J. D., Holm, L., Dahl, M.-L., Alfredsson, L. & Rane, A. (2008). Incidence and predictors of severe bleeding during warfarin treatment. Journal of Thrombosis and Thrombolysis, 25(2), 151-159
Open this publication in new window or tab >>Incidence and predictors of severe bleeding during warfarin treatment
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2008 (English)In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 25, no 2, p. 151-159Article in journal (Refereed) Published
Abstract [en]

Background Optimal warfarin prescription requires correct, individualized assessment of the warfarin-related bleeding risk, which randomised controlled trials may underestimate . Observational studies have reported a range of bleeding risks that differ 40-fold. This variation may be caused by time trends, variation in bleeding definition and study subject selection. We investigated the incidence of, and risk factors for severe bleeding in un-selected warfarin-treated patients from Sweden. Methods Between 2001 and 2005, 40 centres recruited warfarin-naive patients commencing warfarin therapy and followed them prospectively with continuous registration of clinical data. The primary outcome was severe bleeding, according to the WHO universal definition of severe adverse drug reactions. The influence of potential risk factors was investigated by means of a Cox proportional-hazards model. Result A total of 1523 patients contributed 1276 warfarin-exposed patient-years. The incidence of first-time severe bleeding was 2.3 per 100 patient-years (95% confidence interval 1.4 to 3.1). Male sex and use of drugs potentially interacting with warfarin were the only independent risk factors of severe bleeding, with hazard ratios of 2.8 and 2.3, respectively. Age, target International Normalized Ratio (INR), time spent outside target INR range, and warfarin dose requirement were not significantly associated with bleeding risk. Conclusions The risk of severe bleeding in a large naturalistic, prospective cohort of first-time warfarin users was lower than reported in some previous reports. Male gender was an independent predictor of severe bleeding as was the receipt of warfarin-interacting medications at the onset of anticoagulation therapy. Further studies are required to evaluate the effect these findings may have on the quality of current risk-benefit analysis involved in warfarin prescription.

Keywords
warfarin, haemorrhage, adverse drug reactions
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-17188 (URN)10.1007/s11239-007-0048-2 (DOI)000255058800004 ()17514429 (PubMedID)
Available from: 2008-06-17 Created: 2008-06-17 Last updated: 2017-12-08Bibliographically approved
Ceder, G. & Dahl, M.-L. (2008). Trafik och läkemedel. In: FASS 2008 (pp. 2380-2382).
Open this publication in new window or tab >>Trafik och läkemedel
2008 (Swedish)In: FASS 2008, 2008, p. 2380-2382Chapter in book (Other scientific)
Identifiers
urn:nbn:se:uu:diva-17202 (URN)
Available from: 2008-06-17 Created: 2008-06-17
Panagiotidis, G., Arthur, H. W., Lindh, J. D., Dahl, M.-L. & Sjöqvist, F. (2007). Depot haloperidol treatment in outpatients with schizophrenia on monotherapy: impact of CYP2D6 polymorphism on pharmacokinetics and treatment outcome. Therapeutic Drug Monitoring, 29(4), 417-422
Open this publication in new window or tab >>Depot haloperidol treatment in outpatients with schizophrenia on monotherapy: impact of CYP2D6 polymorphism on pharmacokinetics and treatment outcome
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2007 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 29, no 4, p. 417-422Article in journal (Refereed) Published
Abstract [en]

Haloperidol and several other antipsychotic drugs are at least partially metabolized by the polymorphic cytochrome P450 2D6 (CYP2D6). The interindividual variation in metabolic capacity of CYP2D6 might be of importance when dosing. In this study, 26 outpatients with schizophrenia and depot haloperidol as monotherapy were genotyped. The authors found 1 patient with no functional alleles, 8 with one functional allele, 16 with two functional alleles, and 1 with three functional alleles. The daily dose of haloperidol ranged from 0.45 to 14.29 mg. Steady state plasma concentrations were measured at peak (range, 1.6-67 nmol/L) and at trough (range, 1.0-49 nmol/L). The Positive and Negative Syndrome scale for Schizophrenia and the Extrapyramidal Symptom Rating Scale were used to evaluate the clinical effect. The authors found a clear correlation between haloperidol plasma concentration and number of active CYP2D6 alleles. No correlation was found between plasma concentration of haloperidol or number of CYP2D6 alleles and treatment outcome or side effects. A model to predict plasma concentration from dose and number of active CYP2D6 alleles was formed from the obtained data by means of multiple linear regression.

Keywords
CYP2D6, Genotype, Haloperidol, Metabolism, Pharmacokinetics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-17185 (URN)10.1097/FTD.0b013e31811f394d (DOI)000248359200006 ()17667795 (PubMedID)
Available from: 2008-06-17 Created: 2008-06-17 Last updated: 2017-12-08Bibliographically approved
Melkersson, K. I., Scordo, M. G., Gunes, A. & Dahl, M.-L. (2007). Impact of CYP1A2 and CYP2D6 polymorphisms on drug metabolism and on insulin and lipid elevations and insulin resistance in clozapine-treated patients. Journal of Clinical Psychiatry, 68(5), 697-704
Open this publication in new window or tab >>Impact of CYP1A2 and CYP2D6 polymorphisms on drug metabolism and on insulin and lipid elevations and insulin resistance in clozapine-treated patients
2007 (English)In: Journal of Clinical Psychiatry, ISSN 0160-6689, E-ISSN 1555-2101, Vol. 68, no 5, p. 697-704Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Adverse metabolic effects of atypical antipsychotics have increasingly been recognized. Recently, we found that levels of insulin and triglycerides increased by increasing serum clozapine concentration in clozapine-treated patients. As these insulin and triglyceride elevations probably are drug concentration-dependent, they also would be expected to be drug metabolism-related. The genetically polymorphic cytochromes P450 CYP1A2 and CYP2D6 catalyze the metabolism of clozapine. The aim of this study was to evaluate the impact of CYP1A2 and CYP2D6 polymorphisms on serum drug and metabolite levels and on insulin and triglyceride elevations and insulin resistance in patients receiving clozapine. METHOD: Seventeen clozapine-treated patients were genotyped for CYP1A2 and CYP2D6 by polymerase chain reaction-based methods. Serum concentrations of clozapine and its N-desmethylmetabolite, blood glucose, and serum levels of insulin, C-peptide, triglycerides, and cholesterol were analyzed, and homeostasis model assessment index for insulin resistance (HOMA-IR) was determined. RESULTS: Clozapine and N-desmethylclozapine concentration-to-dose (C/D) ratios were significantly higher in patients carrying 2 CYP1A2 single nucleotide polymorphisms (SNPs), previously suggested to cause low enzyme activity, compared to those with no such SNPs (p < .05). In contrast, clozapine and N-desmethylclozapine C/D ratios were not related to the CYP2D6 genotype. Furthermore, patients with elevated insulin levels more frequently carried CYP1A2*1C and/or *1D alleles, had higher clozapine and N-desmethylclozapine C/D ratios, and had higher lipid levels and HOMA-IR, compared to patients with normal insulin levels (p < .05). CONCLUSION: CYP1A2 variants *1C and *1D seem to be associated with higher serum clozapine concentrations and an increased risk of developing insulin and lipid elevations and insulin resistance on a given dose of clozapine.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97082 (URN)000246740300025 ()17503978 (PubMedID)
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2017-12-14Bibliographically approved
Gunes, A., Scordo, M. G., Jaanson, P. & Dahl, M.-L. (2007). Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients. Psychopharmacology, 190(4), 479-484
Open this publication in new window or tab >>Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients
2007 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 190, no 4, p. 479-484Article in journal (Refereed) Published
Abstract [en]

Rationale: Perphenazine, a classical antipsychotic drug, has the potential to induce extrapyramidal side effects (EPS). Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug. Objectives: To evaluate the impact of polymorphisms in the dopamine D 2 and D3 and serotonin 2A and 2C receptor genes (DRD2, DRD3, HTR2A, and HTR2C) on short-term effects of perphenazine monotherapy in schizophrenic patients. Materials and methods: Forty-seven Estonian inpatients were evaluated before and after 4-6 weeks of treatment by Simpson-Angus rating scale, Barnes scale, and Positive and Negative Symptom Scale. Genotyping was performed for common DRD2, DRD3, HTR2A, and HTR2C gene polymorphisms, previously reported to influence receptor expression and/or function. Results: Most of the patients (n = 37) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response. The 102C allele of HTR2A and the -697C and 23Ser alleles of HTR2C were more frequent among patients with EPS (n = 25) compared to patients without EPS (n = 22) (p = 0.02, 0.01, and 0.02, respectively). The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age, gender, and duration of antipsychotic treatment as covariants. There was no significant association between EPS occurrence and polymorphisms in the DRD2 and DRD3 genes. Conclusions: An association was observed between polymorphisms in HTR2A and HTR2C genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy. Larger study populations are needed to confirm our findings.

Keywords
Perphenazine, Receptor gene polymorphisms, Extrapyramidal side effects, Schizophrenia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97080 (URN)10.1007/s00213-006-0622-x (DOI)000243926900008 ()17102980 (PubMedID)
Available from: 2008-04-17 Created: 2008-04-17 Last updated: 2017-12-14Bibliographically approved
Tomson, T., Dahl, M.-L. & Kimland, E. (2007). Therapeutic monitoring of antiepileptic drugs for epilepsy..
Open this publication in new window or tab >>Therapeutic monitoring of antiepileptic drugs for epilepsy.
2007 (English)Report (Other scientific)
Series
Cochrane Database Syst Rev
Identifiers
urn:nbn:se:uu:diva-23728 (URN)17253477 (PubMedID)
Available from: 2008-06-18 Created: 2008-06-18
Ceder, G. & Dahl, M.-L. (2007). Trafik och läkemedel. In: FASS 2007 (pp. 2164-2166).
Open this publication in new window or tab >>Trafik och läkemedel
2007 (Swedish)In: FASS 2007, 2007, p. 2164-2166Chapter in book (Other scientific)
Identifiers
urn:nbn:se:uu:diva-17201 (URN)
Available from: 2008-06-17 Created: 2008-06-17
Sim, S. C., Risinger, C., Dahl, M.-L., Aklillu, E., Christensen, M., Bertilsson, L. & Ingelman-Sundberg, M. (2006). A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants.. Clin Pharmacol Ther, 79(1), 103-13
Open this publication in new window or tab >>A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants.
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2006 (English)In: Clin Pharmacol Ther, ISSN 0009-9236, Vol. 79, no 1, p. 103-13Article in journal (Refereed) Published
Keywords
Animals, Anticonvulsants/pharmacokinetics, Antidepressive Agents/*pharmacokinetics/therapeutic use, Aryl Hydrocarbon Hydroxylases/*genetics, China/epidemiology, Electrophoretic Mobility Shift Assay, Enzyme Inhibitors/*pharmacokinetics/therapeutic use, Ethiopia/epidemiology, Gene Frequency, Genes; Reporter/genetics, Genotype, Humans, Male, Mephenytoin/pharmacokinetics, Mice, Mixed Function Oxygenases/*genetics, Mutation, Omeprazole/pharmacokinetics/therapeutic use, Phenotype, Plasmids/genetics, Proton Pumps/*antagonists & inhibitors, Reverse Transcriptase Polymerase Chain Reaction, Sweden/epidemiology, Transfection, Variation (Genetics)
Identifiers
urn:nbn:se:uu:diva-23734 (URN)16413245 (PubMedID)
Available from: 2008-06-18 Created: 2008-06-18 Last updated: 2011-01-11
Ozdemir, V., Gunes, A., Dahl, M.-L., Scordo, M. G., Williams-Jones, B. & Someya, T. (2006). Could endogenous substrates of drug-metabolizing enzymes influence constitutive physiology and drug target responsiveness?. Pharmacogenomics, 7(8), 1199-1210
Open this publication in new window or tab >>Could endogenous substrates of drug-metabolizing enzymes influence constitutive physiology and drug target responsiveness?
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2006 (English)In: Pharmacogenomics, ISSN 1462-2416, Vol. 7, no 8, p. 1199-1210Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-23729 (URN)17184207 (PubMedID)
Available from: 2007-01-31 Created: 2007-01-31 Last updated: 2011-01-11
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