| 1. |
- Syvänen, Stina, et al.
(författare)
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Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood-brain barrier can be studied with PET
- 2006
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 32:3, s. 1134-1141
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Tidskriftsartikel (refereegranskat)abstract
- Active efflux transporters in the blood-brain barrier lower the brain concentrations of many drug molecules and endogenous substances and thus affect their central action. The objective of this investigation was to study the dynamics of the entire inhibition process of the efflux transporter P-glycoprotein (P-gp), using positron emission tomography (PET). The P-gp marker [C-11]verapamil was administered to anesthetized rats as an i.v. bolus dose followed by graded infusions via a computerized pump system to obtain a steady-state concentration of [C-11]verapamil in brain. The P-gp modulator cyclosporin A (CsA) (3, 10 and 25 mg/kg) was administered as a short bolus injection 30 min after the start of the [C-11]verapamil infusion. The CsA pharmacokinetics was studied in whole blood in a parallel group of rats. The CsA blood concentrations were used as input to model P-gp inhibition. The inhibition of P-gp was observed as a rapid increase in brain concentrations of [C-11]verapamil, with a maximum after 5, 7.5 and 17.5 min for the respective doses. The respective increases in maximal [C-11]verapamil concentrations were 1.5, 2.5 and 4 times the baseline concentration. A model in which CsA inhibited P-gp by decreasing the transport of [C-11]verapamil out from the brain resulted in the best fit. Our data suggest that it is not the CsA concentration in blood, but rather the CsA concentration in an effect compartment, probably the endothelial cells of the blood-brain barrier that is responsible for the inhibition of P-gp.
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| 2. |
- Estrada, Sergio, et al.
(författare)
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[C-11]UCB-A, a novel PET tracer for synaptic vesicle protein 2 A
- 2016
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 43:6, s. 325-332
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Development of a selective and specific high affinity PET tracer, [C-11]UCB-A, for the in vivo study of SV2A expression in humans. Radiochemistry and preclinical studies in rats and pigs including development of a tracer kinetic model to determine V-T. A method for the measurement of percent intact tracer in plasma was developed and the radiation dosimetry was determined in rats. Results: 3-5 GBq of [C-11]UCB-A could be produced with radiochemical purity exceeding 98% with a specific radioactivity of around 65 GBq/mu mol. In vitro binding showed high selective binding towards SV2A. [C-11]UCB-A displayed a dose-dependent and reversible binding to SV2A as measured with PET in rats and pigs and the V-T could be determined by Logan analysis. The dosimetry was favorable and low enough to allow multiple administrations of [C-11]UCB-A to healthy volunteers, and the metabolite analysis showed no sign of labeled metabolites in brain. Conclusions: We have developed the novel PET tracer, [C-11]UCB-A, that can be used to measure SV2A expression in vivo. The dosimetry allows up to 5 administrations of 400 MBq of [C-11]UCB-A in humans. Apart from measuring drug occupancy, as we have shown, the tracer can potentially be used to compare SV2A expression between individuals because of the rather narrow range of baseline V-T values. This will have to be further validated in human studies.
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| 3. |
- Jonasson, My, et al.
(författare)
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Tracer kinetic analysis of (S)-18F-THK5117 as a PET tracer for assessing tau pathology.
- 2016
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 57:4, s. 574-581
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Tidskriftsartikel (refereegranskat)abstract
- Because a correlation between tau pathology and the clinical symptoms of Alzheimer's disease (AD) has been hypothesized, there is increasing interest in developing PET tracers that bind specifically to tau protein. The aim of this study was to evaluate tracer kinetic models for quantitative analysis and generation of parametric images for the novel tau ligand (S)-(18)F-THK5117.METHODS: 9 subjects (5 with AD, 4 with mild cognitive impairment) received a 90 min dynamic (S)-(18)F-THK5117 PET scan. Arterial blood was sampled for measurement of blood radioactivity and metabolite analysis. VOI-based analysis was performed using plasma-input models; single-tissue and two-tissue (2TCM) compartment models and plasma-input Logan, and reference tissue models; simplified reference tissue model (SRTM), reference Logan and standardised uptake value ratio (SUVr). Cerebellum grey matter was used as reference region. Voxel-level analysis was performed using basis function implementations of SRTM, reference Logan and SUVr. Regionally averaged voxel values were compared to VOI-based values from the optimal reference tissue model and simulations were made to assess accuracy and precision. In addition to 90 min, initial 40 and 60 min data were analysed.RESULTS: Plasma-input Logan distribution volume ratio (DVR)-1 values agreed well with 2TCM DVR-1 values (R2=0.99, slope=0.96). SRTM binding potential (BPND) and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 (R2=1.00, slope≈1.00) while SUVr70-90-1 values correlated less well and overestimated binding. Agreement between parametric methods and SRTM was best for reference Logan (R2=0.99, slope=1.03). SUVr70-90-1 values were almost 3 times higher than BPND values in white matter and 1.5 times higher in grey matter. Simulations showed poorer accuracy and precision for SUVr70-90-1 values than for the other reference methods. SRTM BPND and reference Logan DVR-1 values were not affected by a shorter scan duration of 60 min.CONCLUSION: SRTM BPND and reference Logan DVR-1 values were highly correlated with plasma-input Logan DVR-1 values. VOI-based data analyses indicated robust results for scan durations of 60 min. Reference Logan generated quantitative (S)-(18)F-THK5117 DVR-1 parametric images with the greatest accuracy and precision, and with a much lower white matter signal than seen with SUVr-1 images.
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| 4. |
- Windahl, Ulrika, et al.
(författare)
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Development and Validation of a Quantitative UHPLC-MS-MS Method for the Determination of Alpha-Chloralose in Feline Blood and Application on Blood Samples Collected from Cats with Symptoms of Alpha-Chloralose Poisoning
- 2022
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Ingår i: Journal of Analytical Toxicology. - : Oxford University Press. - 0146-4760 .- 1945-2403. ; 46:6, s. 651-657
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-chloralose (AC) is used as a rodenticide as well as an anesthetic agent in laboratory animals. It was previously also used as an avicide. Detection of AC in blood samples or in body tissues collected postmortem is key for the diagnosis of clinical cases and a requirement for surveillance of secondary toxicosis, including potential cases in wild animals. Reports on poisoning of humans and non-laboratory animals confirmed by the detection of AC or its metabolites are available, however poisoning of domestic animals are rarely available. Furthermore, reports on clinical cases in domestic animals rarely report quantifications of AC in blood or body tissues. The present study describes the validation of a quantitative Ultrahigh Performance Liquid Chromatography tandem Mass Spectrometry (UHPLC-MS-MS) method that can be used in cases of suspected AC poisoning in cats. The validation study showed the method to be fit for purpose. In serum, the limit of quantification was 100 ng/mL and the limit of detection was 30 ng/mL. The new analytical method was applied on blood samples collected from 20 individual cats with a preliminary clinical diagnosis of acute AC poisoning. AC was confirmed in all 20 feline blood samples, and the concentration range of AC was 538-17,500 ng/mL. The quantitative method developed in this study was found to be a fast and selective method for confirmation of AC poisoning using blood samples from cats.
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