| 1. |
- Hallberg, Pär, et al.
(author)
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Acute pancreatitis following medical abortion : Case report
- 2004
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In: BMC Women's Health. - : Springer Science and Business Media LLC. - 1472-6874. ; 4:1, s. 1-
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Journal article (other academic/artistic)abstract
- BACKGROUND: Acute pancreatitis rarely complicates pregnancy. Although most pregnant women with acute pancreatitis have associated gallstones, less common causes such as drugs have been reported. CASE PRESENTATION: We report the case of a 34-year-old woman who underwent medical abortion with mifepristone and gemeprost and received codeine as pain-relief during the induction of abortion. She developed a severe acute necrotizing pancreatitis which required 14 days of intensive care. Other possible etiological factors, i.e. gallstone, alcohol intake and hyperlipidemia, were excluded. CONCLUSIONS: The reported case of acute pancreatitis was most likely drug-induced.
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| 2. |
- Schwan, Sofie, et al.
(author)
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A signal for an abuse liability for pregabalin-results from the Swedish spontaneous adverse drug reaction reporting system
- 2010
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In: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 66:9, s. 947-953
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Journal article (peer-reviewed)abstract
- Pregabalin is a gamma-aminobutyric acid (GABA) analogue approved for the treatment of epilepsy, neuropathic pain and generalised anxiety disorder. As a GABA analogue, there has been some concern about an abuse liability. We aimed to investigate the possible abuse liability of pregabalin. By applying a Bayesian data-mining algorithm to reports of possible drug abuse or addiction in the Swedish national register of adverse drug reactions (SWEDIS), we calculated the information component (IC) for pregabalin and reports of abuse and addiction. Out of 198 reports indicative of abuse or addiction to any drug, 16 concerned pregabalin. The IC became significantly elevated in the fourth quarter of 2008, rising to 3.99 (95% confidence interval 3.21-4.59) at the end of 2009. Based on the signal from the present study, we conclude that pregabalin is likely to be associated with an abuse potential.
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| 3. |
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| 4. |
- Alterman, Mathias, et al.
(author)
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P1/P1' modified HIV protease inhibitors as tools in two new sensitive surface plasmon resonance biosensor screening assays
- 2001
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In: European Journal of Pharmaceutical Sciences. - : Elsevier. - 0928-0987 .- 1879-0720. ; 13:2, s. 203-212
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Journal article (peer-reviewed)abstract
- The commonly used HIV-1 protease assays rely on measurements of the effect of inhibitions on the hydrolysis rate of synthetic peptides. Recently an assay based on surface plasmon resonance (SPR) was introduced. We have taken advantage of the fact that the SPR signal is proportional to the mass of the analyte interacting with the immobilised molecule and developed two new improved efficient competition assay methods. Thus, high molecular weight binders were used as amplifiers of the surface plasmon resonance signal. Linkers were attached by a Heck reaction to the para-positions of the P1/P1′ benzyloxy groups of a linear C2-symmetric C-terminal duplicated inhibitor to enable (a) biotin labelling or (b) direct immobilisation of the inhibitor to the biosensor surface matrix. The interaction properties of a series of 17 structurally diverse inhibitors was assessed and compared to previously reported data. The most sensitive assay was obtained by immobilising the enzyme and amplifying the signal with an antibody, giving a detection range between 0.1 nM and 10 μM. Immobilisation of the inhibitor resulted in a stable and durable surface but a narrower detection range (1–100 nM). The two competition assays are anticipated to be very suitable for fast screening of potential HIV inhibitors.
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| 5. |
- Andersson, Margareta A.T., et al.
(author)
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Slag-metal reactions during ladle treatment with focus on desulphurisation
- 2002
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In: Ironmaking & steelmaking. - : Informa UK Limited. - 0301-9233 .- 1743-2812. ; 29:3, s. 224-232
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Journal article (peer-reviewed)abstract
- Within several cooperative projects, KTH (Royal Institute of Technology), Ovako Steel AB, and MEFOS have investigated the desulphurisation of bearing steel during vacuum degassing. The work includes thermodynamic calculations of the slag-metal equilibrium, CFD modelling of slag-metal reactions, and plant trials. Results from the various studies are presented and discussed in this paper. Models for predicting slag properties (sulphide capacity, viscosity, and oxide activities) in liquid slags as functions of slag composition and temperature have been used for the calculation of data which have been employed in static and dynamic modelling of sulphur refining. The results from static modelling show that the method allows fast and easy evaluation of the theoretical desulphurisation conditions during degassing at Ovako Steel AB, as well as theoretical determination of the parameters that have the greatest influence on the equilibrium sulphur distribution. The conclusion from dynamic modelling is that the vacuum degassing operation can be described dynamically with the present knowledge of sulphide capacity, sulphur distribution, viscosity, and oxide activities of ladle slags if this knowledge is combined with fluid flow modelling to derive the overall kinetics. The presented model approaches have been found useful in understanding the sulphur refining process at Ovako Steel AB. The dynamic modelling concept is also believed to have potential for dynamic descriptions of other slag-metal reactions in steelmaking.
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| 6. |
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| 7. |
- Attelind, Sofia, et al.
(author)
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Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events
- 2022
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In: Frontiers in Genetics. - : Frontiers Media S.A.. - 1664-8021. ; 13
-
Journal article (peer-reviewed)abstract
- Apixaban is a direct oral anticoagulant, a factor Xa inhibitor, used for the prevention of ischemic stroke in patients with atrial fibrillation. Despite using recommended dosing a few patients might still experience bleeding or lack of efficacy that might be related to inappropriate drug exposure. We conducted a genome-wide association study using data from 1,325 participants in the pivotal phase three trial of apixaban with the aim to identify genetic factors affecting the pharmacokinetics of apixaban. A candidate gene analysis was also performed for pre-specified variants in ABCB1, ABCG2, CYP3A4, CYP3A5, and SULT1A1, with a subsequent analysis of all available polymorphisms within the candidate genes. Significant findings were further evaluated to assess a potential association with clinical outcome such as bleeding or thromboembolic events. No variant was consistently associated with an altered apixaban exposure on a genome-wide level. The candidate gene analyses showed a statistically significant association with a well-known variant in the drug transporter gene ABCG2 (c.421G > T, rs2231142). Patients carrying this variant had a higher exposure to apixaban [area under the curve (AUC), beta = 151 (95% CI 59-243), p = 0.001]. On average, heterozygotes displayed a 5% increase of AUC and homozygotes a 17% increase of AUC, compared with homozygotes for the wild-type allele. Bleeding or thromboembolic events were not significantly associated with ABCG2 rs2231142. This large genome-wide study demonstrates that genetic variation in the drug transporter gene ABCG2 is associated with the pharmacokinetics of apixaban. However, the influence of this finding on drug exposure was small, and further studies are needed to better understand whether it is of relevance for ischemic and bleeding events.
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| 8. |
- Attelind, Sofia, et al.
(author)
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Identification of risk factors for adverse drug reactions in a pharmacovigilance database
- 2023
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In: Pharmacoepidemiology and Drug Safety. - : John Wiley & Sons. - 1053-8569 .- 1099-1557. ; 32:12, s. 1431-1438
-
Journal article (peer-reviewed)abstract
- Introduction In addition to identifying new safety signals, pharmacovigilance databases could be used to identify potential risk factors for adverse drug reactions (ADRs).Objective To evaluate whether data mining in a pharmacovigilance database can be used to identify known and possible novel risk factors for ADRs, for use in pharmacovigilance practice.Method Exploratory data mining was performed within the Swedish national database of spontaneously reported ADRs. Bleeding associated with direct oral anticoagulants (DOACs)-rivaroxaban, apixaban, edoxaban, and dabigatran-was used as a test model. We compared demographics, drug treatment, and clinical features between cases with bleeding (N = 965) and controls who had experienced other serious ADRs to DOACs (N = 511). Statistical analysis was performed by unadjusted and age adjusted logistic regression models, and the random forest based machine-learning method Boruta.Results In the logistic regression, 13 factors were significantly more common among cases of bleeding compared with controls. Eleven were labelled or previously proposed risk factors. Cardiac arrhythmia (e.g., atrial fibrillation), hypertension, mental impairment disorders (e.g., dementia), renal and urinary tract procedures, gastrointestinal ulceration and perforation, and interacting drugs remained significant after adjustment for age. In the Boruta analysis, high age, arrhythmia, hypertension, cardiac failure, thromboembolism, and pharmacodynamically interacting drugs had a larger than random association with the outcome. High age, cardiac arrhythmia, hypertension, cardiac failure, and pharmacodynamically interacting drugs had odds ratios for bleeding above one, while thromboembolism had an odds ratio below one.Conclusions We demonstrated that data mining within a pharmacovigilance database identifies known risk factors for DOAC bleeding, and potential risk factors such as dementia and atrial fibrillation. We propose that the method could be used in pharmacovigilance for identification of potential ADR risk factors that merit further evaluation.
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| 9. |
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| 10. |
- Bakali, Amin, et al.
(author)
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Crystal structure of YegS, a homologue to the mammalian diacylglycerol kinases, reveals a novel regulatory metal binding site
- 2007
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 282:27, s. 19644-19652
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Journal article (peer-reviewed)abstract
- The human lipid kinase family controls cell proliferation, differentiation, and tumorigenesis and includes diacylglycerol kinases, sphingosine kinases, and ceramide kinases. YegS is an Escherichia coli protein with significant sequence homology to the catalytic domain of the human lipid kinases. We have solved the crystal structure of YegS and shown that it is a lipid kinase with phosphatidylglycerol kinase activity. The crystal structure reveals a two-domain protein with significant structural similarity to a family of NAD kinases. The active site is located in the interdomain cleft formed by four conserved sequence motifs. Surprisingly, the structure reveals a novel metal binding site composed of residues conserved in most lipid kinases.
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| 11. |
- Bejhed, Rebecca S., et al.
(author)
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Identification of Risk Factors for Bisphosphonate-Associated Atypical Femoral Fractures and Osteonecrosis of the Jaw in a Pharmacovigilance Database
- 2016
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In: The Annals of Pharmacotherapy. - : SAGE Publications. - 1060-0280 .- 1542-6270. ; 50:8, s. 616-624
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Atypical femoral fractures (AFs) and osteonecrosis of the jaw (ONJ) are well-known adverse drug reactions (ADRs) associated with bisphosphonates. To prevent these ADRs and to aid in the search for pathogenic mechanisms, knowledge of risk factors can be helpful. Objective: To identify risk factors for bisphosphonate-related ONJ and AF. Methods: In this case-control study of reports of bisphosphonate-related ADRs from February 16, 1984, to October 16, 2013, in the Swedish national database of ADRs, we compared characteristics for cases of ONJ (n = 167) and AF (n = 55) with all other bisphosphonate-related ADRs (n = 565) with regard to demographic variables, clinical characteristics, and concomitant drug treatments. We adjusted for multiple comparisons with Bonferroni correction. Results: Time to onset of ADRs differed statistically significantly between cases of AF and controls (2156 vs 111 days). For ONJ versus controls, differences were statistically significant for time to onset (1240 vs 111 days), intravenous administration (40% vs 20%), dental procedures (49% vs 0.2%) and prostheses (5% vs 0%), cancer disease (44% vs 12%), multiple myeloma (21% vs 1%), rheumatoid arthritis (14% vs 5%), and treatment with antineoplastic agents and oxycodone. Conclusion: These results lend further evidence to previously identified risk factors for ONJthat is, intravenous bisphosphonate administration; invasive dental procedures and dental prostheses; cancer disease, in particular multiple myeloma; and possibly, long-term bisphosphonate treatment. A putative further risk factor is rheumatoid arthritis. Only long-term bisphosphonate treatment was more common among AF cases. The lack of overlap of risk factors between ONJ and AF suggests different pathogenic mechanisms.
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| 12. |
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| 13. |
- Cavalli, Marco, et al.
(author)
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Genome-wide association study of liver enzyme elevation in an extended cohort of rheumatoid arthritis patients starting low-dose methotrexate
- 2022
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In: Pharmacogenomics (London). - : Future Medicine. - 1462-2416 .- 1744-8042. ; 23:15, s. 813-820
-
Journal article (peer-reviewed)abstract
- Aim: A follow-up genome-wide association study (GWAS) in an extended cohort of rheumatoid arthritis (RA) patients starting low-dose methotrexate (MTX) treatment was performed to identify further genetic variants associated with alanine aminotransferase (ALT) elevation. Patients & methods: A GWAS was performed on 346 RA patients. Two outcomes within the first 6 months of MTX treatment were assessed: ALT >1.5-times the upper level of normal (ULN) and maximum level of ALT. Results: SPATA9 (rs72783407) was significantly associated with maximum level of ALT (p = 2.58 × 10-8) and PLCG2 (rs60427389) was tentatively associated with ALT >1.5 × ULN. Conclusion: Associations with SNPs in genes related to male fertility (SPATA9) and inflammatory processes (PLCG2) were identified.
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| 14. |
- Cirulli, Elizabeth T., et al.
(author)
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A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury
- 2019
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In: Gastroenterology. - : W B SAUNDERS CO-ELSEVIER INC. - 0016-5085 .- 1528-0012. ; 156:6, s. 1707-1716
-
Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings.RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 x 10(-9) and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 x 10(-6); allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 x 10(-6); allele frequency = 11.5%). Among amoxicillin-and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A* 02: 01 and DRB1* 15: 01.CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
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| 15. |
- Cismaru, Anca Liliana, et al.
(author)
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Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations
- 2020
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In: Genes. - : MDPI AG. - 2073-4425. ; 11:11
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Journal article (peer-reviewed)abstract
- Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10−7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41–6.68, p = 1.01 × 10−7) and rs4427239 (OR = 5.47, 95%CI: 2.81–10.65, p = 5.75 × 10−7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.
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| 16. |
- Cismaru, Anca Liliana, et al.
(author)
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High-Throughput Sequencing to Investigate Associations Between HLA Genes and Metamizole-Induced Agranulocytosis
- 2020
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In: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 11
-
Journal article (peer-reviewed)abstract
- Background and Objective: Agranulocytosis is a rare and potentially life-threatening complication of metamizole (dipyrone) intake that is characterized by a loss of circulating neutrophil granulocytes. While the mechanism underlying this adverse drug reaction is not well understood, involvement of the immune system has been suggested. In addition, associations between genetic variants in the Human Leukocyte Antigen (HLA) region and agranulocytosis induced by other drugs have been reported. The aim of the present study was to assess whether genetic variants in classical HLA genes are associated with the susceptibility to metamizole-induced agranulocytosis (MIA) in a European population by targeted resequencing of eight HLA genes.Design: A case-control cohort of Swiss patients with a history of neutropenia or agranulocytosis associated with metamizole exposure (n = 53), metamizole-tolerant (n = 39) and unexposed controls (n = 161) was recruited for this study. A high-throughput resequencing (HTS) and high-resolution typing method was used to sequence and analyze eight HLA loci in a discovery subset of this cohort (n = 31 cases, n = 38 controls). Identified candidate alleles were investigated in the full Swiss cohort as well as in two independent cohorts from Germany and Spain using HLA imputation from genome-wide SNP array data. In addition, variant calling based on HTS data was performed in the discovery subset for the class I genes HLA-A, -B, and -C using the HLA-specific mapper hla-mapper.Results: Eight candidate alleles (p < 0.05) were identified in the discovery subset, of which HLA-C∗04:01 was associated with MIA in the full Swiss cohort (p < 0.01) restricted to agranulocytosis (ANC < 0.5 × 109/L) cases. However, no candidate allele showed a consistent association in the Swiss, German and Spanish cohorts. Analysis of individual sequence variants in class I genes produced consistent results with HLA typing but did not reveal additional small nucleotide variants associated with MIA.Conclusion: Our results do not support an HLA-restricted T cell-mediated immune mechanism for MIA. However, we established an efficient high-resolution (three-field) eight-locus HTS HLA resequencing method to interrogate the HLA region and demonstrated the feasibility of its application to pharmacogenetic studies.
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| 17. |
- Englund, Gunilla, et al.
(author)
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Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring
- 2004
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In: BMC Medicine. - : BioMed Central (BMC). - 1741-7015. ; 2:1
-
Journal article (peer-reviewed)abstract
- BackgroundThe ABC transporter P-glycoprotein (P-gp) is recognized as a site for drug-drug interactions and provides a mechanistic explanation for clinically relevant pharmacokinetic interactions with digoxin. The question of whether several P-gp inhibitors may have additive effects has not yet been addressed.MethodsWe evaluated the effects on serum concentrations of digoxin (S-digoxin) in 618 patients undergoing therapeutic drug monitoring. P-gp inhibitors were classified as Class I, with a known effect on digoxin kinetics, or Class II, showing inhibition in vitro but no documented effect on digoxin kinetics in humans. Mean S-digoxin values were compared between groups of patients with different numbers of coadministered P-gp inhibitors by a univariate and a multivariate model, including the potential covariates age, sex, digoxin dose and total number of prescribed drugs.ResultsA large proportion (47%) of the digoxin patients undergoing therapeutic drug monitoring had one or more P-gp inhibitor prescribed. In both univariate and multivariate analysis, S-digoxin increased in a stepwise fashion according to the number of coadministered P-gp inhibitors (all P values < 0.01 compared with no P-gp inhibitor). In multivariate analysis, S-digoxin levels were 1.26 ± 0.04, 1.51 ± 0.05, 1.59 ± 0.08 and 2.00 ± 0.25 nmol/L for zero, one, two and three P-gp inhibitors, respectively. The results were even more pronounced when we analyzed only Class I P-gp inhibitors (1.65 ± 0.07 for one and 1.83 ± 0.07 nmol/L for two).ConclusionsPolypharmacy may lead to multiple drug-drug interactions at the same site, in this case P-gp. The S-digoxin levels increased in a stepwise fashion with an increasing number of coadministered P-gp inhibitors in patients taking P-gp inhibitors and digoxin concomitantly. As coadministration of digoxin and P-gp inhibitors is common, it is important to increase awareness about P-gp interactions among prescribing clinicians.
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| 18. |
- Ericsson, Ola, 1984-
(author)
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An Experimental Study of Liquid Steel Sampling
- 2009
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Licentiate thesis (other academic/artistic)abstract
- Sampling of liquid steel to control the steel making process is very important in the steel industry. However, there are numerous types of disposable samplers and no united standard for sampling. The goal in this study is to investigate the effect of slag protection type and sample geometry on sampling parameters and sample homogeneity. Three sample geometries were selected: i) Björneborg ii) Lollipop with a 6 mm thickness and iii) Lollipop with a 12 mm thickness. These sample geometries have been tested with two types of slag protection: metal-cap-protection and argon-protection. The filling velocity and solidification rate of steel samples have been experimentally measured during plant trials. The sample homogeneity with respect to total oxygen content and inclusion size distribution has been determined in different parts of the samples. The study shows that argon-protected samplers have lower, more even, filling velocities (0.19±0.09 m/s) compared to metal-cap-protected samplers (1.28±2.23 m/s). The solidification rate measurements of the different samplers show that the 6 mm thick Lollipop has the highest solidification rate (99~105 °C/s). Measurements of total oxygen content in argon-protected samples showed little variation between different zones of the samples. However, metal-cap-protected samples contained much higher total oxygen contents. Light optical microscope studies showed that the increase in total oxygen content was probably caused by entrapment of top slag during sampling. Furthermore, it was found that the contamination of top slag in the metal samples increased with a decreased sample weight. Determination of inclusion size distribution in argon-protected Lollipop samples showed that a larger number of primary inclusions are found in the top part compared to the middle and the bottom part of the samples.
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| 19. |
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| 21. |
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| 23. |
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| 24. |
- Fung, P. P. L., et al.
(author)
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Time to onset of bisphosphonate-related osteonecrosis of the jaws : a multicentre retrospective cohort study
- 2017
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In: Oral Diseases. - : WILEY. - 1354-523X .- 1601-0825. ; 23:4, s. 477-483
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Journal article (peer-reviewed)abstract
- Objectives: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients.Subjects and Methods: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012.Results: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n=88) and 2.2years in those treated with zoledronate (n=218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate.Conclusions: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.
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| 25. |
- Ghouse, Jonas, et al.
(author)
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Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors
- 2021
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In: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 78:7, s. 696-709
-
Journal article (peer-reviewed)abstract
- BACKGROUND Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensinconverting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. OBJECTIVES The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema. METHODS A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors #180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. RESULTS The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 x 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 x 10-9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 x 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI:-0.83 to-0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI:-0.46 to-0.05; P = 0.013) blood pressure. CONCLUSIONS In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor-related angioedema.
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| 26. |
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| 29. |
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| 30. |
- Hallberg, Håkan, et al.
(author)
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Investigation of microstructure evolution during self-annealing in thin Cu films by combining mesoscale level set and ab initio modeling
- 2016
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In: Journal of the Mechanics and Physics of Solids. - : Elsevier BV. - 1873-4782 .- 0022-5096. ; 90, s. 160-178
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Journal article (peer-reviewed)abstract
- Microstructure evolution in thin Cu films during room temperature self-annealing is investigated by means of a mesoscale level set model. The model is formulated such that the relative, or collective, influence of anisotropic grain boundary energy, mobility and heterogeneously distributed stored energy can be investigated. Density functional theory (DFT) calculations are performed in the present work to provide the variation of grain boundary energy for different grain boundary configurations. The stability of the predominant (111) fiber texture in the as-deposited state is studied as well as the stability of some special low-Σ grain boundaries. Further, the numerical model allows tracing of the grain size distribution and occurrence of abnormal grain growth during self-annealing. It is found that abnormal grain growth depends mainly on the presence of stored energy variations, whereas anisotropic grain boundary energy or mobility is insufficient to trigger any abnormal growth in the model. However, texture dependent grain boundary properties, mobility in particular, contribute to an increased content of low-Σ boundaries in the annealed microstructure. The increased presence of such boundaries is also promoted by stored energy variations. In addition, if the stored energy variations are sufficient the coexisting (111) and (001) texture components in the as-deposited state will evolve into a (001) dominated texture during annealing. Further, it is found that whereas stored energy variations promote the stability of the (001) texture component, anisotropic grain boundary energy and mobility tend to work the other way and stabilize the (111) component at the expense of (001) grains.
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| 31. |
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| 32. |
- Hallberg, Malin, et al.
(author)
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A new approach to using modelling for on-line prediction of sulphur and hydrogen removal duving ladle refining
- 2004
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In: ISIJ International. - : Iron and Steel Institute of Japan. - 0915-1559 .- 1347-5460. ; 44:8, s. 1318-1327
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Journal article (peer-reviewed)abstract
- A simplified model has been developed for on-line determination of sulphur and hydrogen contents in the steel during vacuum degassing in an ASEA-SKF ladle furnace at Ovako Steel in Hofors, Sweden. The simplified model was developed based on results from fundamental mathematical model simulations of hydrogen and sulphur refining for a number of cases representing normal production situations. More specifically, mass-transfer coefficients were determined from the simulations and thereafter used to develop separate simplified models for sulphur and hydrogen refining. Predictions from using the simplified process models agreed well with sulphur and hydrogen data from full-scale plant trials. It was therefore concluded that the main purpose of the study, namely to achieve a less time-consuming model suitable for production applications, was fulfilled. The final part of the paper presents how the simplified models can provide engineers or operators with off-line or on-line guidelines on performing the vacuum degassing operation such that quality requirements regarding sulphur and hydrogen contents in the steel product are met.
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| 33. |
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| 34. |
- Hallberg, Malin, et al.
(author)
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Sulphur and hydrogen refining during vacuum degassing : a new concept for process control
- 2005
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In: Stahl und Eisen (1881). - 0340-4803. ; 125:5, s. 39-48
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Journal article (peer-reviewed)abstract
- The purpose of this paper is to discuss how a fundamental mathematical model for prediction of hydrogen and sulphur refining during vacuum degassing can be used to develop on-line process control models. It has first been shown how predictions of sulphur and hydrogen using fundamental mathematical models agree well with measured values from plant trials. These models and analytical equations have thereafter been used to predict hydrogen and sulphur refining for new heats. Here, it was shown that these analytical predictions give very similar results as the fundamental predictions. Thus, it is possible to use the analytical equations in production. It is also discussed how the analytical process models can be used both as on-line or off-line tools in industry.
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| 35. |
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| 36. |
- Hallberg, Pär, et al.
(author)
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Adipocyte-derived leucine aminopeptidase genotype and response to antihypertensive therapy
- 2003
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In: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261 .- 1471-2261. ; 18:3, s. 11-
-
Journal article (peer-reviewed)abstract
- BackgroundAdipocyte-derived leucine aminopeptidase (ALAP) is a recently identified member of the M1 family of zinc-metallopeptidases and is thought to play a role in blood pressure control through inactivation of angiotensin II and/or generation of bradykinin. The enzyme seems to be particularly abundant in the heart. Recently, the Arg528-encoding allele of the ALAP gene was shown to be associated with essential hypertension.MethodsWe evaluated the influence of this polymorphism on the change in left ventricular mass index in 90 patients with essential hypertension and echocardiographically diagnosed left ventricular hypertrophy, randomised in a double-blind study to receive treatment with either the angiotensin II type I receptor antagonist irbesartan or the beta1-adrenoceptor blocker atenolol for 48 weeks. Genyotyping was performed using minisequencing.ResultsAfter adjustment for potential covariates (blood pressure and left ventricular mass index at baseline, blood pressure change, age, sex, dose and added antihypertensive treatment), there was a marked difference between the Arg/Arg and Lys/Arg genotypes in patients treated with irbesartan; those with the Arg/Arg genotype responded on average with an almost two-fold greater regression of left ventricular mass index than patients with the Lys/Arg genotype (-30.1 g/m2 [3.6] vs -16.7 [4.5], p = 0.03).ConclusionsThe ALAP genotype seems to determine the degree of regression of left ventricular hypertrophy during antihypertensive treatment with the angiotensin II type I receptor antagonist irbesartan in patients with essential hypertension and left ventricular hypertrophy. This is the first report of a role for ALAP/aminopeptidases in left ventricular mass regulation, and suggests a new potential target for antihypertensive drugs.
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| 37. |
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| 38. |
- Hallberg, Pär, et al.
(author)
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B2 bradykinin receptor (B2BKR) polymorphism and change in left ventricular mass in response to antihypertensive treatment : results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial
- 2003
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In: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 21:3, s. 621-4
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system, including left ventricular (LV) hypertrophy. Studies have demonstrated that bradykinin, through the B2 bradykinin receptor (B2BKR), mediates important cardiovascular effects that may protect against LV hypertrophy. Recently, a +9/-9 exon 1 polymorphism of the B2BKR was shown to be strongly associated with LV growth response among normotensive males undergoing physical training. We aimed to clarify whether the processes found in exercise-induced LV growth in normotensive people also occur in pathological LV hypertrophy. DESIGN AND METHODS: We determined the B2BKR genotype of 90 patients with essential hypertension and echocardiographically diagnosed LV hypertrophy, included in a double-blind study to receive treatment for 48 weeks with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol. RESULTS: B2BKR +9/+9 genotypes responded poorly in LV mass regression, independent of blood pressure reduction or treatment, as compared to the other genotypes (adjusted mean change in LV mass index = -10.0 +/- 4.6 versus -21.6 +/- 2.2 g/m2, P = 0.03). CONCLUSIONS: Our results suggest an impact of the B2BKR polymorphism on LV mass regression during antihypertensive treatment.
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| 39. |
- Hallberg, Pär, et al.
(author)
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Candidate genes in the pharmacogenomics of antihypertensive treatment : a review and future aspects
- 2004
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In: Current Pharmacogenomics. - : Bentham Science Publishers Ltd.. - 1570-1603. ; 2:1, s. 83-112
-
Research review (other academic/artistic)abstract
- Diversity in response to antihypertensive therapy is well-documented. Among many variables in the biological system, reasons include the genetic make-up of individuals. Although individual human genomes are 99.9% identical, the 0.1% difference predicts as many as three million polymorphisms. Some will affect protein expression or function, resulting in phenotypes affected for disease or with altered drug response. Pharmacogenomics focuses on the link between polymorphism in genes and variable response to drugs. The genetic approach to the study of the mechanisms underlying hypertension has led to the identification of some quantitative trait loci or genes that influence blood pressure regulation. An ultimate goal of pharmacogenomic knowledge is to advance beyond the current approach to antihypertensive drug therapy to more individualized approaches. Drugs that are more specific for the molecular characteristics of individual patients should contribute to greater efficacy and reduced toxicity. In this article, we review the pathophysiology of essential hypertension, the principles of its drug treatment, and those pharmacogenomic studies of antihypertensive treatment which, to our knowledge, have been published so far and which deals primarily with two aspects: the blood pressure lowering effect and the regression of left ventricular hypertrophy. Also, a selection of functional polymorphisms in potential candidate genes which have not yet appeared in pharmacogenomic studies of antihypertensive treatment but in various ways have been linked to hypertension and / or its related diseases / organ damages are discussed.
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| 40. |
- Hallberg, Pär, et al.
(author)
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Comparison of Clinical Factors Between Patients With Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema and Cough
- 2017
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In: The Annals of Pharmacotherapy. - Thousand Oaks, USA : Sage Publications. - 1060-0280 .- 1542-6270. ; 51:4, s. 293-300
-
Journal article (peer-reviewed)abstract
- Background: Angioedema is a rare and serious adverse drug reaction (ADR) to angiotensin-converting enzyme (ACE) inhibitor treatment. Dry cough is a common side effect of ACE inhibitors and has been identified as a possible risk factor for angioedema.Objective: We compared characteristics between patients with ACE inhibitor-induced angioedema and cough with the aim of identifying risk factors that differ between these adverse events.Methods: Data on patients with angioedema or cough induced by ACE inhibitors were collected from the Swedish database of spontaneously reported ADRs or from collaborating clinicians. Wilcoxon rank sum test, Fisher's exact test, and odds ratios (ORs) with 95% CIs were used to test for between-group differences. The significance threshold was set to P <0.00128 to correct for multiple comparisons.Results: Clinical characteristics were compared between 168 patients with angioedema and 121 with cough only. Smoking and concomitant selective calcium channel blocker treatment were more frequent among patients with angioedema than cough: OR = 4.3, 95% CI = 2.1-8.9, P = 2.2 × 10(-5), and OR = 3.7, 95% CI = 2.0-7.0, P = 1.7 × 10(-5) Angioedema cases were seen more often in male patients (OR = 2.2, 95% CI = 1.4-3.6, P = 1.3 × 10(-4)) and had longer time to onset and higher doses than those with cough (P = 3.2 × 10(-10) and P = 2.6 × 10(-4)). A multiple model containing the variables smoking, concurrent calcium channel blocker treatment, male sex, and time to onset accounted for 26% of the variance between the groups.Conclusion: Smoking, comedication with selective calcium channel blockers, male sex, and longer treatment time were associated with ACE inhibitor-induced angioedema rather than cough.
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| 41. |
- Hallberg, Pär, et al.
(author)
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Cystatin C vs creatinine as markers of renal function in patients on digoxin treatment
- 2004
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In: Upsala Journal of Medical Sciences. - 0300-9734 .- 2000-1967. ; 109:3, s. 247-253
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Journal article (other academic/artistic)abstract
- BACKGROUND: The kidney function is a major determinant of the serum concentration of digoxin as this drug is mainly eliminated unchanged through the kidneys. Since digoxin is widely prescribed among the elderly, and the glomerular filtration rate (GFR) declines with age, it is important that the clinician takes the patient's GFR into account when prescribing digoxin. Serum cystatin C has been suggested to be superior to creatinine for estimation of GFR, which may have relevance for the optimization of treatment with digoxin. METHODS: To evaluate which of the two GFR markers serum creatinine and serum cystatin C that best correlates with serum digoxin, we compared the serum levels of digoxin with the serum levels of creatinine and cystatin C in 149 patients on therapeutic drug monitoring of digoxin at our hospital. RESULTS: Overall, there was a stronger correlation between serum digoxin concentrations and cystatin C (p=0.00001) as compared to creatinine (p= 0.00003). Interestingly, of the patients with a serum digoxin concentration > or = 1.5 nmol/L, 29% had a serum creatinine level within normal limits, as compared to 20% with normal cystatin C levels. CONCLUSIONS: In this study, serum cystatin C correlated better to serum digoxin than did serum creatinine. With improved GFR monitoring, digoxin concentrations should be better controlled.
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| 42. |
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| 43. |
- Hallberg, Pär, et al.
(author)
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Digoxin and mortality in atrial fibrillation : a prospective cohort study
- 2007
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In: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 63:10, s. 959-971
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study showed that rhythm-control treatment of patients with atrial fibrillation (AF) offered no survival advantage over a rate-control strategy. In a subgroup analysis of that study, it was found that digoxin increased the death rate [relative risk (RR) = 1.42), but it was suggested that this may have been attributable to prescription of digoxin for patients at greater risk of death, such as those with congestive heart failure (CHF). No study has investigated a priori the effect of digoxin on mortality in patients with AF. This study aimed to address this question. METHODS: Using data from the Registry of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA), we studied the 1-year mortality among patients admitted to coronary care units with AF, CHF, or AF+CHF with or without digoxin (n = 60,764) during 1995-2003. Adjustment for differences in background characteristics and other medications and treatments was made by propensity scoring. RESULTS: Twenty percent of patients with AF without CHF in this cohort were discharged with digoxin. This group had a higher mortality rate than the corresponding group not given digoxin [adjusted RR 1.42 (95% CI 1.29-1.56)], whereas no such difference was seen among patients with CHF with or without AF, although these patients had a nearly three-times higher mortality. CONCLUSION: The results suggest that long-term therapy with digoxin is an independent risk factor for death in patients with AF without CHF.
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| 44. |
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| 45. |
- Hallberg, Pär, et al.
(author)
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Gender-specific association between preproendothelin-1 genotype and reduction of systolic blood pressure during antihypertensive treatment : results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA)
- 2004
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In: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 27:5, s. 287-290
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Studies suggest that endothelin-1 contributes to the pathogenesis of hypertension. A G5665T gene polymorphism of preproendothelin-1 has been shown to be associated with higher blood pressure in overweight patients. No study has yet determined the effect of this polymorphism on the change in blood pressure during antihypertensive treatment.HYPOTHESIS:This study aimed to determine this effect in hypertensive patients with left ventricular (LV) hypertrophy during antihypertensive treatment with either irbesartan or atenolol.METHODS: We determined the preproendothelin-1 genotype using minisequencing in 102 patients with essential hypertension and LV hypertrophy verified by echocardiography, randomized in a double-blind fashion to treatment with either the AT1-receptor antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol.RESULTS:The change in systolic blood pressure (SBP) after 12 weeks of treatment was related to the preproendothelin-1 genotype in men; after adjustment for potential covariates (age, blood pressure, and LV mass index at study entry, dose of irbesartan/atenolol, and type of treatment), those carrying the T-allele responded on average with a more than two-fold greater reduction than those with the G/G genotype (-21.9 mmHg [13.9] vs. -8.9 [2.3], p = 0.007). No significant differences in blood pressure change between G/G and carriers of the T-allele were seen among women.CONCLUSIONS:Our finding suggests a gender-specific relationship between the G5665T preproendothelin-1 polymorphism and change in SBP in response to antihypertensive treatment with irbesartan or atenolol, suggesting the endothelin pathway to be a common mechanism included in the hypertensive action of the drugs.
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| 46. |
- Hallberg, Pär, et al.
(author)
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Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough : a genome-wide association study in a Swedish population
- 2017
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In: Pharmacogenomics (London). - : FUTURE MEDICINE LTD. - 1462-2416 .- 1744-8042. ; 18:3, s. 201-213
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Journal article (peer-reviewed)abstract
- Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes iden-tified in previous studies. Patients & methods: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 x 10(-8). Results: We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 x 10(-8)). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. Conclusion: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.
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| 47. |
- Hallberg, Pär, et al.
(author)
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Genetic variants associated with antithyroid drug-induced agranulocytosis : a genome-wide association study in a European population
- 2016
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In: The Lancet Diabetes and Endocrinology. - 2213-8587 .- 2213-8595. ; 4:6, s. 507-516
-
Journal article (peer-reviewed)abstract
- Background: Drug-induced agranulocytosis is a potentially life-threatening adverse reaction. Genome-wide association studies (GWASs) in ethnic Chinese people in Taiwan and Hong Kong have shown an association between agranulocytosis induced by antithyroid drugs and the HLA alleles HLA-B*38:02 and HLA-DRB1*08:03. We aimed to identify genetic variants associated with antithyroid drug-induced agranulocytosis in a white European population.Methods: We did a GWAS in 234 European adults with any non-chemotherapy drug-induced agranulocytosis (absolute neutrophil count <= 0.5 x 10(9)/L [<= 500/mu L]) and 5170 population controls. 39 of the 234 patients had agranulocytosis that was induced by antithyroid drugs (thiamazole [methimazole], carbimazole, or propylthiouracil). After imputation and HLA allele prediction, 9 380 034 single nucleotide polymorphisms (SNPs) and 180 HLA alleles were tested for association. The genome-wide significance threshold was p<5 x 10(-8).Findings: Agranulocytosis induced by non-chemotherapy drugs in general was significantly associated with the HLA region on chromosome 6, with odds ratios (ORs) of 3.24 (95% CI 2.31-4.55, p = 1.20 x 10(-11)) for HLA-B*27:05 and 3.57 (2.61-4.90, p = 2.32 x 10(-15)) for the top SNP (rs114291795). Drug-specific analysis showed that the association with HLA-B*27: 05 was largely driven by cases induced by antithyroid drugs. In a multiple logistic regression model, the OR for HLA-B*27: 05 was 7.30 (3.81-13.96) when antithyroid drug-induced agranulocytosis was compared with population controls (p= 1.91 x 10(-9)) and 16.91 (3.44-83.17) when compared with a small group of hyperthyroid controls (p = 5.04 x 10(-4)). Three SNPs were strongly associated with antithyroid drug-induced agranulocytosis: rs652888 (OR 4.73, 95% CI 3.00-7.44, p= 1.92 x 10(-11)) and rs199564443 (17.42, 7.38-41.12, p = 7.04 x 10(-11)), which were independent of HLA-B*27:05, and rs1071816 (5.27, 3.06-9.10, p = 2.35 x 10(-9)) which was in moderate linkage disequilibrium with HLA-B*27:05. In heterozygous carriers of all three SNPs, the predicted probability of antithyroid drug-induced agranulocytosis was about 30% (OR 753, 95% CI 105-6812). To avoid one case of agranulocytosis, based on the possible risk reduction if all three SNPs are genotyped and carriers are treated or monitored differently from non-carriers, roughly 238 patients would need to be genotyped.Interpretation: In white European people, antithyroid drug-induced agranulocytosis was associated with HLA-B* 27: 05 and with other SNPs on chromosome 6. In the future, carriers of these variants could be placed under intensified monitoring or offered alternative treatment for hyperthyroidism.
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| 48. |
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| 49. |
- Hallberg, Pär, 1974-, et al.
(author)
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Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival
- 2019
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In: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 40, s. 595-604
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy.METHODS: We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation.FINDINGS: Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002.INTERPRETATION: We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.
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| 50. |
- Hallberg, Pär, 1974-
(author)
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Pharmacogenomics of Antihypertensive Treatment & Clinical Pharmacological Studies of Digoxin Treatment
- 2005
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Doctoral thesis (other academic/artistic)abstract
- In Part I we found that the CYP2C9 genotype appears to influence the diastolic blood pressure response to the angiotensin II-receptor antagonist irbesartan in patients with hypertension and left ventricular hypertrophy. Those with the *1/*2 genotype (slower metabolism) responded better than those with the *1/*1 genotype (normal metabolism), likely due to a slower elimination of the drug. We further found that a +9/-9 exon 1 polymorphism of the B2 bradykinin receptor gene – shown to affect mRNA expression - appears to influence the regression of left ventricular mass during therapy with irbesartan or the beta-blocker atenolol in the same patients. Subjects with the -9/-9 genotype (higher mRNA expression) had a greater regression than carriers of the +9 allele. In Part II we found that women on digoxin therapeutic drug monitoring have higher serum digoxin concentrations (SDCs) as compared to men (1.54±0.04 [nmol/L±SE] vs 1.20±0.05 [nmol/L±SE], p<0.001), which could be of importance since an SDC >1.4 nmol/L has been associated with increased mortality. We further found that coadministration of P-glycoprotein inhibitors with digoxin was common (47%) among the same patients, and that the SDC increased in a stepwise fashion with the number of P-glycoprotein inhibitors (20-60%). Lastly, we found that patients admitted to Swedish coronary care units with atrial fibrillation without heart failure and who had been given digoxin had a higher 1-year mortality than those not given digoxin (RR 1.44 [95% CI 1.29-1.60], adjustment made for potential confounders). In conclusion, Part I represents a further step in the pharmacogenomic prospect of tailoring antihypertensive therapy. Part II indicates that heightened attention to the digoxin-dose is warranted in women, that there is a need for awareness about P-glycoprotein interactions with digoxin, and that long-term therapy with digoxin is an independent risk factor for death among patients with atrial fibrillation without heart failure.
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