| 1. |
- Albrekt, Ann-Sofie, et al.
(författare)
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Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency
- 2014
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Ingår i: Bmc Pharmacology & Toxicology. - : Springer Science and Business Media LLC. - 1471-2210 .- 2050-6511. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Due to the recent European legislations posing a ban of animal tests for safety assessment within the cosmetic industry, development of in vitro alternatives for assessment of skin sensitization is highly prioritized. To date, proposed in vitro assays are mainly based on single biomarkers, which so far have not been able to classify and stratify chemicals into subgroups, related to risk or potency. Methods: Recently, we presented the Genomic Allergen Rapid Detection (GARD) assay for assessment of chemical sensitizers. In this paper, we show how the genome wide readout of GARD can be expanded and used to identify differentially regulated pathways relating to individual chemical sensitizers. In this study, we investigated the mechanisms of action of a range of skin sensitizers through pathway identification, pathway classification and transcription factor analysis and related this to the reactive mechanisms and potency of the sensitizing agents. Results: By transcriptional profiling of chemically stimulated MUTZ-3 cells, 33 canonical pathways intimately involved in sensitization to chemical substances were identified. The results showed that metabolic processes, cell cycling and oxidative stress responses are the key events activated during skin sensitization, and that these functions are engaged differently depending on the reactivity mechanisms of the sensitizing agent. Furthermore, the results indicate that the chemical reactivity groups seem to gradually engage more pathways and more molecules in each pathway with increasing sensitizing potency of the chemical used for stimulation. Also, a switch in gene regulation from up to down regulation, with increasing potency, was seen both in genes involved in metabolic functions and cell cycling. These observed pathway patterns were clearly reflected in the regulatory elements identified to drive these processes, where 33 regulatory elements have been proposed for further analysis. Conclusions: This study demonstrates that functional analysis of biomarkers identified from our genomics study of human MUTZ-3 cells can be used to assess sensitizing potency of chemicals in vitro, by the identification of key cellular events, such as metabolic and cell cycling pathways.
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| 2. |
- Vilhelmsson, Andreas, et al.
(författare)
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Experiences from consumer reports on psychiatric adverse drug reactions with antidepressant medication : a qualitative study of reports to a consumer association
- 2012
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Ingår i: BMC Pharmacology. - : BioMed Central. - 1471-2210. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe new European pharmacovigilance legislation has been suggested as marking the beginning of a new chapter in drug safety, making patients an important part of pharmacovigilance. In Sweden since 2008 it has been possible for consumers to report adverse drug reactions (ADRs) to the Medical Products Agency (MPA), and these reports are now understood as an increasingly valuable contribution in the monitoring of safety aspects in medicines. Already in 2002 it was possible to report experiences with medicines to the non-profit and independent organization Consumer Association for Medicines and Health (KILEN) through a web-based report form with an opportunity to describe ADR experiences in free text comments. The aim of this study was to qualitatively analyze the free text comments appended to consumer reports on antidepressant medication.MethodsAll reports of suspected adverse reactions regarding antidepressant medications submitted from January 2002 to April 2009 to KILEN’s Internet-based reporting system in Sweden were analyzed according to reported narrative experience(s). Content analysis was used to interpret the content of 181 reports with free text comments.ResultsThree main categories emerged from the analyzed data material: (1) Experiences of drug treatment with subcategories (a) Severe psychiatric adverse reactions, and (b) Discontinuation symptoms; (2) Lack of communication and (3) Trust and distrust. A majority of the reports to KILEN were from patients experiencing symptoms of mental disturbances (sometimes severe) affecting them in many different ways, especially during discontinuation. Several report included narratives of patients not receiving information of potential ADRs from their doctor, but also that there were no follow-ups of the treatment. Trust was highlighted as especially important and some patients reported losing confidence in their doctor when they were not believed about the suspected ADRs they experienced, making them attempt to discontinue their antidepressant treatment on their own.ConclusionsThe present study indicates that free text comments as often contained in case reports directly submitted by patients can be of value in pharmacovigilance and provide important information on how a drug may affect the person using it and influence his or her personal life.
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| 3. |
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| 4. |
- Malmsjö, Malin, et al.
(författare)
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Potent P2Y6 receptor mediated contractions in human cerebral arteries
- 2003
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Ingår i: BMC Pharmacology. - : Springer Science and Business Media LLC. - 1471-2210. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Extracellular nucleotides play an important role in the regulation of vascular tone and may be involved in cerebral vasospasm after subarachnoidal haemorrhage. This study was designed to characterise the contractile P2 receptors in endothelium-denuded human cerebral and omental arteries. The isometric tension of isolated vessel segments was recorded in vitro. P2 receptor mRNA expression was examined by RT-PCR. RESULTS: In human cerebral arteries, the selective P2Y6 receptor agonist, UDPbetaS was the most potent of all the agonists tested (pEC50 = 6.8 PlusMinus; 0.7). The agonist potency; UDPbetaS > alphabeta-MeATP > UTPgammaS > ATPgammaS > ADPbetaS = 0, indicated the presence of contractile P2X1 P2Y2, P2Y4 and P2Y6, but not P2Y1 receptors, in human cerebral arteries. In human omental arteries, UDPbetaS was inactive. The agonist potency; alphabeta-MeATP > ATPgammaS = UTPgammaS > ADPbetaS = UDPbetaS = 0, indicated the presence of contractile P2X1, and P2Y2 receptors, but not P2Y1 or P2Y6 receptors, in human omental arteries. RT-PCR analysis of endothelium-denuded human cerebral and omental arteries demonstrated P2X1, P2Y1, P2Y2 and P2Y6 receptor mRNA expression. There were no bands for the P2Y4 receptor mRNA in the omental arteries, while barely detectable in the cerebral arteries. CONCLUSIONS: P2Y6 receptors play a prominent role in mediating contraction of human cerebral arteries. Conversely, no such effect can be observed in human omental arteries and previous results confirm the absence of P2Y6 receptors in human coronary arteries. The P2Y6 receptor might be a suitable target for the treatment of cerebral vasospasm.
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| 5. |
- Berggard, Cecilia, et al.
(författare)
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Brainstem levels of transcription factor AP-2 in rat are changed after treatment with phenelzine, but not with citalopram
- 2005
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Ingår i: BMC Pharmacology. - : Springer Science and Business Media LLC. - 1471-2210. ; 5, s. 1-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Before therapeutic effect is obtained after treatment with antidepressant drugs, like serotonin selective reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAO-Is) there is an initial lag-period of a few weeks. Neuronal adaptations on a molecular level are supposed to be involved in the initiation of the antidepressant effect. Transcription factor AP-2 is essential for neuronal development and many genes involved in the brainstem monoaminergic systems have binding sites for AP-2 in their regulatory regions. The genotype of the AP-2beta isoform has been associated with e.g. anxiety-related personality traits and with platelet MAO activity. In addition, previous studies have shown that the levels of AP-2alpha and AP-2beta in rat whole brain were decreased after 10 days of treatment with citalopram (SSRI) and imipramine (TCA), and were increased with phenelzine (MAO-I). RESULTS: In the present study, we report that treatment with citalopram for 1, 7 or 21 days did not have effect on the AP-2 levels in rat brainstem. However, after treatment with phenelzine for 1, 7 or 21 days the levels of AP-2alpha and AP-2beta had increased after 7 days, but had returned to control levels at day 21. CONCLUSION: The decrease in AP-2 levels in rat whole brain previously seen after treatment with citalopram does not seem to be localised to the brainstem, it may rather occur in the monoaminergic terminal projection areas. The present data suggest that the increase in AP-2 levels previously seen in rat whole brain after subchronic treatment with phenelzine is located in the brainstem. It cannot, however, be excluded that other brain regions are involved.
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| 6. |
- Eggertsen, Robert, 1948, et al.
(författare)
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No changes of cholesterol levels with a commercially available glucosamine product in patients treated with lipid lowering drugs: a controlled, randomised, open cross-over trial.
- 2012
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Ingår i: BMC pharmacology & toxicology. - : Springer Science and Business Media LLC. - 2050-6511. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Background: The widespread use of natural health products is also a problem, as they could interact with prescribed drugs in patients. One commonly used product is glucosamine for osteoarthritis and some reports have found increased values of cholesterol and other lipids in patients treated with simvastatin for hypercholesterolemia. The aim of this trial was to investigate the effects of glucosamine on s-cholesterol levels (total s-cholesterol, s-HDL, s-LDL) in primary care patients on treatment with simvastatin or atorvastatin. Methods: Controlled, randomized, open, crossover pharmacodynamic study in two primary health care centres. Patients were treated with ArtroxW (glucosamine) 625 mg twice daily and control (a commercially available multivitamin tablet VitamineralW). The study started with a run-in period of four weeks followed by control or active treatment with randomization of sealed envelopes. Each treatment period was four weeks and the treatment with simvastatin or atorvastatin was unchanged during the study (12 weeks). 34 patients were treated with a stable dose of simvastatin (n=21) or atorvastatin (n=13) for at least three months. Assessments of total s-cholesterol, s-HDL, S-LDL and s-triglycerides were performed in the morning with the patients in a fasting condition. T-tests for paired samples were used for statistical analyses and a p-value <0.05 was considered significant. Endpoints were the differences in lipid values at week 8 and week 12. Results: All patients completed the study. No significant changes were seen on any of lipid levels in the simvastatin group. Conclusion: The actual glucosamine product did not change lipid levels of patients treated with simvastatin. Atorvastatin group was too small for safe calculations but was also without changes. Trial registration: EUDRACT2006-001458-28
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| 7. |
- Gustafsson, Maria, et al.
(författare)
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Inappropriate long-term use of antipsychotic drugs is common among people with dementia living in specialized care units
- 2013
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Ingår i: BMC pharmacology & toxicology. - : Springer Science and Business Media LLC. - 2050-6511. ; 14, s. 10-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Antipsychotic drugs are widely used for the treatment of Behavioral and Psychological Symptoms of Dementia (BPSD), despite their limited efficacy and concerns about safety. The aim of this study was to describe antipsychotic drug therapy among people with dementia living in specialized care units in northern Sweden.METHODS: This study was conducted in 40 specialized care units in northern Sweden, with a total study population of 344 people with dementia. The study population was described in regard to antipsychotic drug use, ADL function, cognitive function and BPSD, using the Multi-Dimensional Dementia Assessment Scale (MDDAS). These data were collected at baseline and six months later. Detailed data about antipsychotic prescribing were collected from prescription records.RESULTS: This study showed that 132 persons (38%) in the study population used antipsychotic drugs at the start of the study. Of these, 52/132 (39%) had prescriptions that followed national guidelines with regard to dose and substance.After six months, there were 111 of 132 persons left because of deaths and dropouts. Of these 111 people, 80 (72%) were still being treated with antipsychotics, 63/111 (57%) with the same dose. People who exhibited aggressive behavior (OR: 1.980, CI: 1.515-2.588), or passiveness (OR: 1.548, CI: 1.150-2.083), or had mild cognitive impairment (OR: 2.284 CI: 1.046-4.988), were at increased risk of being prescribed antipsychotics.CONCLUSION: The prevalence of antipsychotic drug use among people with dementia living in specialized care units was high and inappropriate long-term use of antipsychotic drugs was common.
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| 8. |
- Gustafsson, Maria, et al.
(författare)
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Psychotropic drug use among people with dementia - a six-month follow-up study
- 2013
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Ingår i: BMC Pharmacology & Toxicology. - : BioMed Central. - 2050-6511. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Psychotropic drugs are widely used among old people with dementia but few studies have described long-term treatment in this group of patients. The purpose of this study was to explore the long-term use of psychotropic drugs in old people with dementia.METHODS: Data on psychotropic drug use, functioning in the activities of daily living (ADL), cognitive function and behavioral and psychological symptoms were collected at baseline and six months later, using the Multi-Dimensional Dementia Assessment Scale (MDDAS). The data were collected in 2005-2006. Detailed data about the prescribing of psychotropic drugs were collected from prescription records. This study was conducted in 40 specialized care units in northern Sweden, with a study population of 278 people with dementia.RESULTS: At the start of the study, 229 of the participants (82%) were prescribed at least one psychotropic drug; 150 (54%) used antidepressants, 43 (16%) used anxiolytics, 107 (38%) used hypnotics and sedatives, and 111 (40%) used antipsychotics. Among the baseline users of antidepressants, anxiolytics, hypnotics and sedatives and antipsychotics, 67%, 44%, 57% and 57% respectively, still used the same dose of the same psychotropic drug after six months. Associations were found between behavioral and psychological symptoms and different psychotropic drugs.CONCLUSION: Psychotropic drug use was high among people with dementia living in specialized care units and in many cases the drugs were used for extended periods. It is very important to monitor the effects and adverse effects of the prescribed drug in this frail group of people.
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| 9. |
- Jiang, Lin, et al.
(författare)
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Haloperidol changes mRNA expression of a QKI splice variant in human astrocytoma cells.
- 2009
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Ingår i: BMC pharmacology. - : Springer Science and Business Media LLC. - 1471-2210. ; 9, s. 6-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The quaking homolog, KH domain RNA binding (mouse) (QKI) is a candidate gene for schizophrenia. Disturbed QKI mRNA expression is observed in the prefrontal cortex of patients, and some of these changes correlate to treatment with antipsychotic drugs.To test if low doses of antipsychotic drugs can modify QKI mRNA expression, human astrocytoma (U343) and oligodendroglioma (HOG) cell lines were treated with five different antipsychotic drugs including Haloperidol, Aripiprazole, Clozapine, Olanzapine and Risperidone. Messenger RNA expression levels of splice variants QKI-5, QKI-6 and QKI-7 were measured by Real-Time PCR. RESULTS: Haloperidol treatment (0.2 microM) doubled QKI-7 mRNA levels in U343 cells after 6 hours (p-value < 0.02). The effect was dose dependent, and cells treated with ten times higher concentration (2 microM) responded with a five-fold and three-fold increase in QKI-7, 6 and 24 hours after treatment, respectively (p-values < 0.0001). CONCLUSION: The results in U343 cells suggest that QKI-7 mRNA expression in human astrocytes is induced by Haloperidol, at concentrations similar to plasma levels relevant to clinical treatment of schizophrenia. The molecular mechanism of action of antipsychotic drugs after binding to receptors is not well known. We hypothesize that QKI regulation is involved in this mechanism.
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