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| 2. |
- Andersson, Patrik, et al.
(författare)
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Toxicity with LXR agonists – Problem solving activities for mechanistic understanding
- 2012
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Ingår i: Toxicology Letters. - Shannon : Elsevier. - 0378-4274 .- 1879-3169. ; 211:Suppl. (S), s. S39-S39
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Tidskriftsartikel (refereegranskat)abstract
- Several lines of evidence points toward the potential positive effects of LXR (Liver X Receptor) modulators for effective and safe therapy of cardiovascular diseases (CVDs). LXR is a dimeric nuclear hormone receptor that exists as a combination of RXR and one of two subtypes LXR alpha or beta, which act as cholesterol sensors. LXR alpha is highly expressed in the liver, intestine and adipose tissue while LXR beta is ubiquitously expressed. Activation of LXR up-regulates several genes involved in reverse cholesterol transport (RCT), including ABC transporters. This results in increased efflux of cholesterol from macrophages in atherosclerotic vascular lesions to the circulation and further on to other tissues to ultimately be excreted into the faeces. These effects together with systemic and local anti-inflammatory properties of LXR modulation are likely to contribute to decreased atherosclerosis. The positive effects of LXR activation on RCT and cholesterol balance must be obtained without negative lipid effects, since LXR also activates lipogenic genes. Other types of toxicity and approaches to better understand the mechanism(s) behind these will be presented. Copyright © 2012 Published by Elsevier Ireland Ltd.
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| 3. |
- Burestedt, E., et al.
(författare)
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Optimisation and validation of an automated solid phase extraction technique coupled on-line to enzyme-based biosensor detection for the determination of phenolic compounds in surface water samples
- 1995
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Ingår i: Chromatographia. - Heidelberg : Springer Berlin/Heidelberg. - 0009-5893 .- 1612-1112. ; 41:3-4, s. 207-215
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Tidskriftsartikel (refereegranskat)abstract
- A fully integrated screening system for phenolic compounds was developed incorporating on-line solid phase extraction, fractionation and biosensor detection. Two different types of biosensors, solid graphite and carbon paste electrodes incorporating the enzyme tyrosinase, were compared and used in the screening system. Interfacing of the solid phase extraction and fractionation with the biosensor detection was given special attention since the biosensors were not compatible with the organic modifier used for desorption of phenols from the solid phase extraction step. The system was validated with conventional analytical techniques. Surface water samples from the Ebro river were spiked with 1,10, and 25μg L−1 of catechol, phenol,p-cresol, respectively. Three out of seven samples were spiked and the correct samples were identified, containing phenols equivalent to the spiked concentrations. © 1995 Friedr. Vieweg & Sohn Verlagsgesellschaft mbH.
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| 4. |
- Desbans, Coraline, et al.
(författare)
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Accurate prediction of variability in CLint and Fm via 3A4 is only obtained by assessing a series of individual cryopreserved human hepatocyte batches
- 2010
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Ingår i: Drug metabolism reviews (Softcover ed.). - New York : Informa Healthcare. - 0360-2532 .- 1097-9883. ; 42:Suppl. 1, s. 274-274
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Tidskriftsartikel (refereegranskat)abstract
- Multiple in-vitro and in-vivo methods are currently assessed and under discussion to predict human clearance and pharmacokinetics from preclinical studies. A combination of high fm with a high fraction metabolism via a single pathway, e.g. via CYP3A4 (fmCYP3A4), has been recognized as a high risk factor for Drug Drug Interactions (DDI) in the clinical setting[1],[2],[3],[4] . Thus, an early predictive tool to allow for appropriate modeling of this potential risk for DDI is highly warranted. Hepatocytes, capable of both phase I and phase II reactions, are an attractive system to study fraction metabolized (fm) via a single pathway. In the present study, intrinsic clearance (CLint) was determined in cryopreserved human hepatocytes in suspension for a set of five compounds with known and variable fm via CYP3A4 (amitriptyline, loratadine, methylprednisolone, midazolam, and tacrolimus) in the absence or presence of ketoconazole. In order to get an insight into the influence of inter-individual variability, twelve batches of cryopreserved human hepatocytes with either high, moderate or low CYP3A4-dependent activity towards midazolam (MDZ) were chosen. Clint values were determined as substrate depletion under shaking conditions (900rpm) using an elliptic shaker as previously reported[5]. For all compounds, the mean CLint for individual donors in absence of ketoconazole correlated very well with literature data on the mean of individual donors1,2,3, and/or pools of donors5. Average fmCYP3A4 for midazolam was 83%, tacrolimus 64%, methylprednisolone 55%, amitriptyline 28%, and loratadine 19% are also well within the literature data2,3,4. Interestingly, the results obtained for a homogenous subpopulation regarding MDZ CLint and percent inhibition by ketoconazole, were not directly related to the ketoconazole sensitive CLint for the other CYP3A4 substrates tested. The variability in CYP3A4 contribution for compounds having multiple metabolic pathways cannot be predicted by the fm3A4 for MDZ. This suggests that an overall prediction of CLint or fm via CYP3A4 for compounds partially metabolized by this enzyme is not possible. Thus, the individual differences in CLint for a given compound and fmCYPi can only be well covered by assessing a series of individual cryopreserved human hepatocyte batches.[1] Lu, C., Miwa, G. T., Prakash, S. R., Gan, L-S. and Balani, S. K. (2007), Drug Metabolism And Disposition, 35: 1, 79–85[2] Lu, C., Hatsis,P., Berg,C., Lee, F. W. and Balani, S. K. (2008), Drug Metabolism And Disposition, 36: 7, 1255–1260[3] Lu, C., Hatsis,P., Berg,C., Lee, F. W. and Balani, S. K. (2008), Drug Metabolism And Disposition, 36: 7, 1261–1266[4] Emoto, C., Murase, S. and Iwasaki, K.(2006), Xenobiotica, 36: 8, 671 — 683[5] Simon ,S., Blanchard, N., Alexandre, E., Hewitt, N. J., Bachellier, P., Heyd, B., Coassolo, P., Schuler, F., Richert, L., (2009) ‘MV-HUF Copenhagen’
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| 5. |
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| 6. |
- Johannesson, Petra, et al.
(författare)
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SAR and optimization of trioxoisothiazole-based liver receptor X (LXR) agonists leading to the clinical candidate AZD3971
- 2014
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Ingår i: Division of Medicinal Chemistry. ; , s. 247-247
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Konferensbidrag (refereegranskat)abstract
- The liver X receptors (LXRα and LXRβ) are members of the nuclear receptor family of transcription factors. The activation of LXR induces genes involved in reverse cholesterol transport (RCT), which is believed to be the main effect of LXR agonists in the prevention or treatment of atherosclerosis. However LXR agonists have also been shown to cause hepatic steatosis and hypertriglyceridaemia. The ability to separate beneficial effects from negative effects has been a challenge that so far has hampered the development of LXR agonists for human use. We herein describe the SAR and optimization of a series of trioxoisothiazole-based LXR agonists leading to compounds with nanomolar potencies and a separation of beneficial versus negative effects in vivo. This work ultimately led to the nomination of AZD3971 as a candidate for the treatment of atherosclerosis.
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| 7. |
- Larsson, Marita, et al.
(författare)
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Transient isotachophoresis for sensitivity enhancement in capillary electrophoresis-mass spectrometry for peptide analysis
- 2000
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Ingår i: Electrophoresis. - Weinheim : Wiley-VCH Verlagsgesellschaft. - 0173-0835 .- 1522-2683. ; 21:14, s. 2859-2865
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Tidskriftsartikel (refereegranskat)abstract
- Transient isotachophoresic (ITP) focusing was used for the on-line analysis of peptides by capillary zone electrophoresis-mass spectrometry (CZE-MS), allowing injection volumes of up to 0.9 microL. A sheath liquid electrospray interface was used with a single quadrupole mass analyzer. First, the technique was applied to the qualitative analysis of a tryptic digest of cytochrome c, resulting in low-background, high-quality spectra. Second, the linear range was investigated by selected ion monitoring (SIM) for a peptidomimetic direct thrombin inhibitor melagatran (Mr 429.5) and two endogenous peptides, substance P (Mr 1348) and calcitonin gene-related peptide (alpha-CGRP; Mr 3806).
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| 8. |
- Lutz, Mareike, 1967-, et al.
(författare)
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Applying hollow fibres for separating free and bound label in continuous-flow immunochemical detection
- 1996
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Ingår i: Journal of Chromatography A. - Amsterdam : Elsevier B.V. - 0021-9673 .- 1873-3778. ; 755:2, s. 179-187
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Tidskriftsartikel (refereegranskat)abstract
- On-line liquid chromatography-immunochemical detection (LC-ICD) provides the possibility to individually monitor cross-reactive compounds overcoming the need of tedious fraction collection. ICD is performed as a post-column reaction detection system and is based on a two-step immunoreaction. In the first step unlabelled antibodies are added to the LC effluent and allowed to react with antigens (analytes) eluting from the LC column. The amount of analytes bound to the antibodies is measured by adding, in a second step, labelled antigen to the reaction mixture. For quantitation, free and bound label need to be separated prior to detection. The present paper describes a hollow fibre module (HFM), which can be used for this purpose. Separation of free and bound label occurs on discrimination by size. Using biotin as a model compound, a detection limit of 30 nmol/l can be reached employing anti-biotin antibodies and a low-molecular-mass fluorescence label in the LC-ICD system. Additional to low-molecular-mass labels, the HFM allows the use of small enzyme labels. In this context, horseradish peroxidase-labelled biotin was used as a label in combination with antibodies in the immunochemical detection of biotin. This allows future implementation of commercially available enzyme immunoassay kits in continuous-flow immunochemical detection.
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| 9. |
- Lutz, Mareike, 1967-, et al.
(författare)
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Biochemical detection for direct bead surface analysis
- 1997
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Ingår i: Analytical Chemistry. - Washington : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 69:23, s. 4878-4884
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Tidskriftsartikel (refereegranskat)abstract
- A continuous-now biochemical detection system is presented which recognizes biologically active compounds immobilized to solid phases. This approach can be used to screen, for example, solid-phase combinatorial libraries for lead compounds. Biochemical detection is performed by mixing a plug of a solid-phase suspension with labeled affinity protein, During a short reaction time, the labeled affinity protein will only bind to ligands, i.e., compounds with biological activity. Hereafter, the free and bound labels are separated by means of a hollow fiber module, Quantitation of the free label is performed with a conventional now-through fluorescence detector, Total assay time amounts to less than 3 min. Biochemical detection for direct bead surface analysis was developed for two model systems. The first model system used fluorescence-labeled avidin as affinity protein and its ligands biotin and iminobiotin immobilized to agarose as analytes. The second model system used fluorescence-labeled antisheep (Fab)(2) fragments as affinity protein and different IgGs immobilized to agarose as analytes. The feasibility of this approach for recognition of solid-phase immobilized ligands was documented by screening 50 samples with a 100% hit rate.
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| 10. |
- Lutz, Mareike, 1967-, et al.
(författare)
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Development and Optimization of a Solid Composite Tyrosinase Biosensor for Phenol Detection in Flow Injection Systems
- 1996
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Ingår i: Electroanalysis. - Weinheim : Wiley-VCH Verlagsgesellschaft. - 1040-0397 .- 1521-4109. ; 8:2, s. 117-123
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Tidskriftsartikel (refereegranskat)abstract
- Bulk-modified epoxy-graphite tyrosinase biosensors were fabricated by four different procedures. The influence of these fabrication procedures on the analytical performance of the enzyme electrode in an amperometric wall-jet flow cell has been studied. The bioprobe performance is assessed by cyclic voltammetry. Higher current densities and narrower peaks were obtained when the enzyme was introduced in the dry state into the epoxy-graphite material, instead of introducing it previously dissolved in the buffer. In the FI system responses of 11.79 μA cm-2 and 1.43 μA cm-2 are then obtained for catechol and phenol respectively for 50 μL injections of 20 μM solutions. Moreover, if gold/palladium is introduced into the epoxy-graphite, a further increase in current is achieved resulting in 27.70 μA cm-2 and 4.90 μA cm-2 for catechol and phenol, respectively. This biosensor can operate in aqueous as well as in mixed aqueous-organic environments.
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