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- Oxenstierna, G, et al.
(författare)
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Increased frequency of aberrant CSF circulation in schizophrenic patients compared to healthy volunteers
- 1996
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Ingår i: European psychiatry : the journal of the Association of European Psychiatrists. - : Cambridge University Press (CUP). - 0924-9338. ; 11:1, s. 16-20
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Tidskriftsartikel (refereegranskat)abstract
- In a previous cisternographic study of the cerebrospinal fluid (CSF) circulation in schizophrenic patients, indications for disturbed flow dynamics were found in 10 of 30 subjects. In order to replicate and investigate the clinical and pathophysiological significance of this finding, 39 schizophrenic patients and 42 healthy subjects were examined with an improved method for measurement of CSF circulation. 99mTc-DTPA was injected intrathecally and the gamma cisternograms were evaluated blindly. Correlations between cisternography findings and age, duration of disease, previous hospitalizations, positive or negative symptomatology, exposure to neuroleptics, psychiatric family history, CT findings and CSF levels of protein, tryptophan and monoamine metabolites, were calculated. Seven of the patients showed abnormalities in the cisternograms with a slow or obstructed flow of CSF over the convexities (P < 0.01) whereas none of the healthy volunteers showed abnormalities. There were no correlations between disturbed CSF circulation in the patients and the clinical and biochemical parameters, thus the significance of the deviations, similar to other biological aberrations found in schizophrenic patients, is not known. Recent developments in magnetic resonance imaging offer new possibilities to further examine CSF circulation abnormalities in schizophrenia.
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| 6. |
- Ståhlberg, F., et al.
(författare)
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Method for quantification of low flow velocities by magnetic resonance phase imaging.
- 1986
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Ingår i: Acta Radiologica. Supplementum. - 0365-5954. ; 369, s. 486-489
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to compare the influence of flow in the velocity range 0 to 25 mm/s on modulus, phase, real and imaginary images obtained with a standard magnetic resonance scanner (Siemens Magnetom, 0.5 T), and to develop a simple method for determination of flow velocities in vivo from this information. Using a flow phantom, the flow dependent magnetic resonance imaging (MRI) signal has been studied as a function of flow perpendicular to the image slice with non-doped water (simulating moving cerebrospinal fluid) as well as with water doped with Mn2+ (simulating moving blood) for each of the four mentioned image types. The results show a marked flow dependence on all types of images studied. The variation of the signal with flow in the modulus images is relaxation-time dependent in the studied velocity range and it is non-monotone for non-doped water. In the phase images, however, the variations are monotone and not dependent on relaxation times. In modulus images the curve shape is relatively independent on flow direction, while phase images are clearly dependent on flow direction in the studied velocity range. The signal versus velocity curves for the real and imaginary images show resemblance to those for the modulus and the phase images, respectively. It is concluded that the phase information can be used to generate a signal versus velocity calibration curve, which can be used to quantify low flow velocities in vivo.
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| 8. |
- Bergstrand, Martin, 1977-, et al.
(författare)
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A semi-mechanistic model for characterization of regional absorption properties and prospective prediction of plasma concentrations following administration of new modified release formulations
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Methods to study in vivo gastro intestinal (GI) transit and/or regional absorption of pharmaceuticals are available and increasingly used in drug development. A modelling approach to utilize the information generated in such studies for prospective predictions of absorption from newly developed modified release formulations was outlined and tested for the investigational drug AZD0837. This work was a natural extension to the companion article “A semi-mechanistic model to link in vitro and in vivo drug release for modified release formulations”. The drug release model governed the amount of substance released in distinct GI regions over time. GI distribution of released drug substance, region specific rate and extent of absorption and the influence of concomitant food intake were estimated with the model. The model was informed by data from a magnetic marker monitoring study and an intubation study with local administration in colon. Disposition estimates were further supported by observations following administration of oral solution and intravenous infusion of AZD0837. Distinctly different absorption properties were characterized for different GI regions. Bioavailability over the gut-wall was estimated to be high for substance released in the stomach and absorbed in duodenum (70%) compared to substance released and absorbed in the small intestine (25%). Bioavailability was once again higher in colon (70%) but on the other hand considerably slower than in the earlier parts of the GI tract. The established model was largely successful in predicting plasma concentration following administration of three newly developed formulations for which no clinical data had been applied during model building.
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| 9. |
- Bergstrand, Martin, 1977-, et al.
(författare)
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A semi-mechanistic model to link in vitro and in vivo drug release for modified release formulations
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- In vivo prediction of drug release based on in vitro experiments is important for the development of new modified release (MR) formulations. Most efforts to improve such predictions have focused on altering the in vitro experiments to more resemble the in vivo conditions. A novel approach is evaluated in the present article where a computer model is established and used to link results from standard static in vitro experiment to in vivo predictions. A nonlinear mixed-effects model describing the in vitro drug release for 6 closely related hydrophilic matrix based MR formulations across different experimental conditions (pH, rotation speed and ionic strength) was developed. This model was applied to in vivo observations of drug release and tablet gastro intestinal (GI) position assessed with Magnetic Marker Monitoring (MMM). By combining the MMM observations with literature information on pH and ionic strength along the GI tract, the mechanical stress in different parts of the GI tract could be estimated in units equivalent to rotation speed in the in vitro set-up (USP 2 apparatus). The mechanical stress in the upper stomach was estimated to be 94 rpm and 134 rpm in the lower stomach. For the small intestine and colon the estimates of mechanical stress was 93 and 38 rpm respectively. Predictions of in vivo drug release including expected between subject/tablet variability could be made for other newly developed formulations based on the drug release model combined with a model describing tablet GI transit. This exemplifies a modeling approach that can be utilized to predict in vivo behavior from standard in vitro experiments and support formulation development and quality control of MR formulations.
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| 10. |
- Bergstrand, Martin, 1977-, et al.
(författare)
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A semi-mechanistic modeling strategy for characterization of regional absorption properties and prospective prediction of plasma concentrations following administration of new modified release formulations
- 2012
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Ingår i: Pharmaceutical research. - : Springer Science+Business Media B.V.. - 0724-8741 .- 1573-904X. ; 29:2, s. 574-584
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE To outline and test a new modeling approach for prospective predictions of absorption from newly developed modified release formulations based on in vivo studies of gastro intestinal (GI) transit, drug release and regional absorption for the investigational drug AZD0837. METHODS This work was a natural extension to the companion article "A semi-mechanistic model to link in vitro and in vivo drug release for modified release formulations". The drug release model governed the amount of substance released in distinct GI regions over time. GI distribution of released drug substance, region specific rate and extent of absorption and the influence of food intake were estimated. The model was informed by magnetic marker monitoring data and data from an intubation study with local administration in colon. RESULTS Distinctly different absorption properties were characterized for different GI regions. Bioavailability over the gut-wall was estimated to be high in duodenum (70%) compared to the small intestine (25%). Colon was primarily characterized by a very slow rate of absorption. CONCLUSIONS The established model was largely successful in predicting plasma concentration following administration of three newly developed formulations for which no clinical data had been applied during model building.
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