| 1. |
- Romeo, Alessandro, 1961, et al.
(författare)
-
A wavelet add-on code for new-generation N-body simulations and data de-noising (JOFILUREN)
- 2004
-
Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 354:4, s. 1208-1222
-
Tidskriftsartikel (refereegranskat)abstract
- Wavelets are a new and powerful mathematical tool, whose most celebrated applications are data compression and de‐noising. In a previous paper, we have shown that wavelets can be used for removing noise efficiently from cosmological, galaxy and plasma N‐body simulations. The expected two‐orders‐of‐magnitude higher performance means, in terms of the well‐known Moore's law, an advance of more than one decade in the future. In this paper, we describe a wavelet add‐on code designed for such an application. Our code can be included in common grid‐based N‐body codes, is written in fortran, is portable and is available on request from the first author. The code can also be applied for removing noise from standard data, such as signals and images.
|
|
| 2. |
- Ederoth, Per, et al.
(författare)
-
Blood-brain barrier transport of morphine in patients with severe brain trauma
- 2004
-
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 57:4, s. 427-435
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: In experimental studies, morphine pharmacokinetics is different in the brain compared with other tissues due to the properties of the blood-brain barrier, including action of efflux pumps. It was hypothesized in this clinical study that active efflux of morphine occurs also in human brain, and that brain injury would alter cerebral morphine pharmacokinetics. METHODS: Patients with traumatic brain injury, equipped with one to three microdialysis catheters in the brain and one in abdominal subcutaneous fat for metabolic monitoring, were studied. The cerebral catheter locations were classified as 'better' and 'worse' brain tissue, referring to the degree of injury. Morphine (10 mg) was infused intravenously over a 10-min period in seven patients in the intensive care setting. Tissue and plasma morphine concentrations were obtained during the subsequent 3-h period with microdialysis and regular blood sampling. RESULTS: The area under the concentration-time curve (AUC) ratio of unbound morphine in brain tissue to plasma was 0.64 (95% confidence interval 0.40, 0.87) in 'better' brain tissue (P < 0.05 vs. the subcutaneous fat/plasma ratio), 0.78 (0.49, 1.07) in 'worse' brain tissue and 1.00 (0.86, 1.13) in subcutaneous fat. The terminal half-life and T(max) were longer in the brain vs. plasma and fat, respectively. The relative recovery for morphine was higher in 'better' than in 'worse' brain tissue. The T(max) value tended to be shorter in 'worse' brain tissue. CONCLUSIONS: The unbound AUC ratio below unity in the 'better' human brain tissue demonstrates an active efflux of morphine across the blood-brain barrier. The 'worse' brain tissue shows a decrease in relative recovery for morphine and in some cases also an increase in permeability for morphine over the blood-brain barrier.
|
|
| 3. |
|
|
| 4. |
- Jonsson, E Niclas, et al.
(författare)
-
Population pharmacokinetics of levosimendan in patients with congestive heart failure
- 2003
-
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 55:6, s. 544-551
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents. METHODS: Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined. RESULTS: A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg. CONCLUSIONS: The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.
|
|
| 5. |
- Kerbusch, Thomas, et al.
(författare)
-
Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability
- 2003
-
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 56:6, s. 639-652
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: A model describing the population pharmacokinetics of darifenacin and its hydroxylated metabolite was developed from a combined analysis of 18 studies. The relationships between explanatory covariates and pharmacokinetic parameters were explored. METHODS: Plasma concentration data from 337 individuals were pooled from 17 Phase 1 studies (median 28/33 darifenacin/metabolite observations per healthy subject), and one Phase 2 study (median 7/7 darifenacin/metabolite observations per subject) encompassing one intravenous and five different oral formulations (1-45 mg). RESULTS: Non-linear Mixed Effects Models (NONMEM Version VI) described both the population pharmacokinetics of darifenacin and its hydroxylated metabolite with a two-compartment disposition model with first order absorption. The values (mean +/- standard error of the mean) for clearance (CL) and volume of distribution of the central compartment were 40.2 +/- 2.0 l h-1 and 34.7 +/- 4.6 l h-1, respectively, in a typical male CYP2D6 homozygote-extensive metabolizer (Hom-EM). The absolute bioavailability (F) of darifenacin in a Hom-EM after doses of 7.5, 15 or 30 mg extended release formulation (CR) was 15, 19 and 25%, respectively. Factors influencing F were formulation (70-110% higher for CR compared with immediate release following equivalent daily doses), CYP2D6 genotype [heterozygote-extensive metabolizers (Het-EM) and poor metabolizers (PM) experienced 40 and 90%, respectively, higher exposure than Hom-EM irrespective of dose administered] and saturable first-pass metabolism (dose nonlinearity 1.05-1.43-fold). Race affected F, which was 56% lower in Japanese males. The CYP3A4 inhibitors ketoconazole and erythromycin increased F to approximately 100% and ketoconazole decreased CL by 67.5%. CL was 31% lower in females and 10% lower at night. Formulation affected the metabolite absorption/formation rate. Ketoconazole and erythromycin administration resulted in a decrease of 61.2 and 28.8% in exposure to the metabolite, respectively. The covariates race, gender and circadian rhythm accounted for only approximately half of the variability in the estimated exposures to darifenacin. CONCLUSIONS: The pooled analysis provided a descriptive integration of all characteristics and covariates of the pharmacokinetics of darifenacin and its metabolite, enabling interpolation and extrapolation of these key factors.
|
|
| 6. |
- Klockhoff, H, et al.
(författare)
-
Faster absorption of ethanol and higher peak concentration in women after gastric bypass surgery
- 2002
-
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 54:6, s. 587-591
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate the absorption, distribution and elimination of ethanol in women with abnormal gut as a result of gastric bypass surgery. Patients who undergo gastric bypass for morbid obesity complain of increased sensitivity to the effects of alcohol after the operation. Methods: Twelve healthy women operated for morbid obesity at least 3 years earlier were recruited. Twelve other women closely matched in terms of age and body mass index (BMI) served as the control group. After an overnight fast each subject drank 95% v/v ethanol (0.30 g kg-1 body weight) as a bolus dose. The ethanol was diluted with orange juice to 20% v/v and finished in 5 min. Specimens of venous blood were taken from an indwelling catheter before drinking started and every 10 min for up to 3.5 h post-dosing. The blood alcohol concentration (BAC) was determined by headspace gas chromatography. Results: The maximum blood-ethanol concentration (Cmax) was 0.741 ▒ 0.211 g l-1 (▒ s.d.) in the operated group compared with 0.577 ▒ 0.112 g l-1 in the controls (mean difference 0.164 g l-1, 95% confidence interval (CI) 0.021, 0.307). The median time to peak (tmax) was 10 min in the bypass patients compared with 30 min in controls (median difference -15 min (95% CI -10, -20 min). At 10 and 20 min post-dosing the BAC was higher in the bypass patients (P < 0.05) but not at 30 min and all later times (P > 0.05). Other pharmacokinetic parameters of ethanol were not significantly different between the two groups of women (P > 0.05). Conclusions: The higher sensitivity to ethanol after gastric bypass surgery probably reflects the more rapid absorption of ethanol leading to higher Cmax and earlier tmax. The marked reduction in body weight after the operation might also be a factor to consider if the same absolute quantity of ethanol is consumed.
|
|
| 7. |
|
|
| 8. |
- Zingmark, Per-Henrik, et al.
(författare)
-
Pharmacokinetic/pharmacodynamic models for the depletion of Vβ5.2/5.3 T cells by the monoclonal antibody ATM-027 in patients with multiple sclerosis, as measured by FACS
- 2004
-
Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 58:4, s. 378-89
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: (i) To model the effects of the monoclonal antibody ATM-027 on the number of target cells and on the receptor density on the cell surface as measured by Fluorescence Activated Cell Sorter analysis, (ii) to investigate the effects of categorizing a continuous scale, and (iii) to simulate a phase II trial from phase I data in order to evaluate the predictive performance of the model by comparison with the actual trial results. METHODS: Based on the data from one phase I and one phase II study in multiple sclerosis (MS) patients, models were developed to characterize the pharmacokinetics and pharmacodynamics of the monoclonal antibody ATM-027 and its effects on Vbeta5.2/5.3+ T cells. The pharmacodynamic variables were the number of target T cells and the expression of its receptor. The latter was modelled in both a categorical and continuous way. The modelling was performed with a nonlinear mixed effects approach using the software NONMEM. The joint continuous models were used to simulate the phase II trial from the phase I data. RESULTS: The pharmacokinetics of ATM-027 were characterized by a two-compartment model with a total volume of distribution of 5.9 litres and a terminal half-life of 22.3 days (phase II parameter estimates) in the typical patient. Continuous receptor expression was modelled using an inhibitory sigmoidal Emax-model. Similar results from the phase I and phase II data were obtained, and EC50 was estimated to be 138 and 148 microg litre(-1), respectively. Categorical receptor expression was modelled using a proportional odds model, and the EC50 values obtained were highly correlated with those from the continuous model. The numbers of target T cells were also modelled and treatment with ATM-027 decreased the number of cells to 25.7% and 28.9% of their baseline values in the phase I and II trials, respectively. EC50s for the decrease in the number of T cells were 83 microg litre(-1) and 307 microg litre(-1), respectively. Simulations of the phase II trial from the phase I models gave good predictions of the dosing regimens administered in the phase II study. CONCLUSION: All aspects of effects of the monoclonal antibody ATM-027 on Vbeta5.2/5.3+ T cells were modelled and the phase II trial was simulated from phase I data. The effects of categorizing a continuous scale were also evaluated.
|
|
| 9. |
|
|
| 10. |
|
|
