| 1. |
- Ahlström, Christine, et al.
(författare)
-
Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions
- 2011
-
Ingår i: JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS. - 1567-567X. ; 38:1, s. 1-24
-
Tidskriftsartikel (refereegranskat)abstract
- A feedback model was developed to describe the tolerance and oscillatory rebound seen in non-esterified fatty acid (NEFA) plasma concentrations following intravenous infusions of nicotinic acid (NiAc) to male Sprague-Dawley rats. NiAc was administered as an intravenous infusion over 30 min (0, 1, 5 or 20 μmol kg(-1) of body weight) or over 300 min (0, 5, 10 or 51 μmol kg(-1) of body weight), to healthy rats (n = 63), and serial arterial blood samples were taken for measurement of NiAc and NEFA plasma concentrations. Data were analyzed using nonlinear mixed effects modeling (NONMEM). The disposition of NiAc was described by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. The plasma concentration of NiAc was driving NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. The NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M (1)) inhibited the formation of R and the last compartment (M ( N )) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. The potency, IC (50), of NiAc was 45 nmol L(-1), the fractional turnover rate k ( out ) was 0.41 L mmol(-1) min(-1) and the turnover rate of moderator k ( tol ) was 0.027 min(-1). A lower physiological limit of NEFA was modeled as a NiAc-independent release (k ( cap )) of NEFA into plasma and was estimated to 0.032 mmol L(-1) min(-1). This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc. The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues.
|
|
| 2. |
- Fall, David, 1983, et al.
(författare)
-
Modelling cracking and bending failure of SFRC beams with conventional reinforcement
- 2013
-
Ingår i: 8th International Conference on Fracture Mechanics of Concrete and Concrete Structures. - 9788494100413 ; , s. 1276-1285
-
Konferensbidrag (refereegranskat)abstract
- In this study three beams, with varying contents of steel fibre reinforcement, were tested in four point bending and compared with results from FE-analysis. The beams were part of a larger experimental programme where relevant material properties were investigated. FE-modelling was performed using a two dimensional model. Concrete was represented by four-node quadrilateral isoperimetric plane stress elements. The smeared crack approach was utilized and the stress-strain relation describing the tensile behavior of the concrete was calculated from uni-axial test results, assuming the crack bandwidth to be equal to the element length. In compression, the concrete was assumed to behave elasto ideal-plastic. The reinforcement was modelled by straight 2-node truss elements connected to the concrete by two-dimensional interface elements providing the bond-slip properties. A material model including hardening effects was derived from tension tests of reinforcement bars and used for modelling the conventional reinforcement. A multi-linear bond-slip model was established through pull-out tests. As an alternative, analyses were also performed taking into account a reduction of the bond stress after yielding of the reinforcement occurred. Loading was applied in two phases: the first comprehending only the self-weight, while incremental loading was applied by deformation control during the second phase. General agreement between experiments and FE-analyses was obtained with regard to load-displacement behaviour. By observing the crack patterns, both from FE-analysis and experiments, it can be concluded that the general behaviour agreed; however, in the analyses not all cracks were fully localized. A higher degree of crack localization was obtained when the bond loss at yielding was included.
|
|
| 3. |
- Fall, David, 1983, et al.
(författare)
-
Non-linear Finite Element Analysis of Steel Fibre Reinforced Beams with Conventional Reinforcement
- 2012
-
Ingår i: 8th RILEM International Symposium on Fiber Reinforced Concrete: challenges and opportunities (BEFIB 2012). - 9782351581322 ; , s. 1033-1045
-
Konferensbidrag (refereegranskat)abstract
- The purpose of this study has been to investigate the behavior of elements reinforced with both conventional steel reinforcement and steel fibres in order to support future applications of such composites. Three beams of varying fibre content were tested in four-point bending. The results were then compared with results from nonlinear FE-analyses and the calculation method suggested in fib Model Code 2010. The beams were a part of a larger experimental programme where relevant properties were investigated in uniaxial tension tests and pull-out tests. The FE-modeling was performed using a two dimensional plane stress model. General agreement between experiments and the FE-analyses was obtained with regard to load-displacement behavior. The crack patterns from the FE-analysis and experiments agreed in general, although the crack patterns in the analysis were more distributed close to the reinforcement. Crack localization was enhanced by modifying the bond-slip behavior to include the bond loss at yielding. Calculations in accordance with fib Model Code 2010 yield conservative results in comparison with both experiments and FE-analysis.
|
|
| 4. |
- Jansson Löfmark, Rasmus, 1979, et al.
(författare)
-
Determination of eflornithine enantiomers in plasma by precolumn derivatization with o-phthalaldehyde-N-acetyl-l-cysteine and liquid chromatography with UV detection
- 2010
-
Ingår i: BMC Biomedical chromotography. - : Wiley. - 0269-3879 .- 1099-0801. ; 24:7, s. 768-773
-
Tidskriftsartikel (refereegranskat)abstract
- A bioanalytical method for indirect determination of eflornithine enantiomers in 75 mu L human plasma has been developed and validated. L- and D-eflornithine were derivatized with o-phthalaldehyde and N-acetyl-L-cysteine to generate diastereomers which were separated on two serially connected Chromolith Performance columns (RP-18e 100 x 4.6 mm i.d.) by a isocratic flow followed by a gradient flow for elution of endogenous compounds. The diastereomers were detected with UV (340 nm). The between-day precisions for L- and D-eflornithine in plasma were 8.4 and 2.3% at 3 mu m, 4.0 and 5.1% at 400 mu m, and 2.0 and 3.7% at 1000 mu m. The lower limit of quantification was determined to be 1.5 mu m, at which precision was 14.9 and 9.9% for 1- and D-eflornithine, respectively.
|
|
| 5. |
- Johansson, Carl-Christer, et al.
(författare)
-
Population pharmacokinetic modeling and deconvolution of enantioselective absorption of eflornithine in the rat.
- 2013
-
Ingår i: Journal of pharmacokinetics and pharmacodynamics. - : Springer Science and Business Media LLC. - 1573-8744 .- 1567-567X. ; 40:1, s. 117-28
-
Tidskriftsartikel (refereegranskat)abstract
- Enantioselective pharmacokinetics and absorption of eflornithine in the rat was investigated using population pharmacokinetic modeling and a modified deconvolution method. Bidirectional permeability of L- and D-eflornithine was investigated in Caco-2 cells. The rat was administered racemic eflornithine hydrochloride as a single oral dose [40-3,000 mg/kg bodyweight (BW)] or intravenously (IV) (100-2,700 mg/kg BW infused over 60-400 min). Serial arterial blood samples were collected and L- and D-eflornithine were quantitated with a previously published chiral bioanalysis method. The D:L concentration ratio was determined in rat faeces. Intravenous L-and D-eflornithine plasma concentration-time data was analyzed using population pharmacokinetic modeling and described with a 3-compartment pharmacokinetic model with saturable binding to one of the peripheral compartments. Oral plasma concentration-time data was analyzed using a modified deconvolution method accounting for nonlinearities in the eflornithine pharmacokinetics. Clearance was similar for both enantiomers (3.36 and 3.09 mL/min). Oral bioavailability was estimated by deconvolution at 30 and 59% for L- and D-eflornithine. The D:L concentration ratio in feces was 0.49 and the Caco-2 cell permeability was similar for both enantiomers (6-10 × 10(-8) cm/s) with no evident involvement of active transport or efflux. The results presented here suggest that the difference in the bioavailability between eflornithine enantiomers is caused by a stereoselective difference in extent rather than rate of absorption. The presented modified deconvolution method made it possible to account for the non-linear component in the suggested three-compartment pharmacokinetic model thus rapidly estimating eflornithine oral bioavailability.
|
|
