| 1. |
- Agerso¸, Henrik, et al.
(författare)
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The dosing solution influence on the pharmacokinetics of degarelix, a new GnRH antagonist, after s.c. administration to beagle dogs.
- 2003
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 20:3, s. 335-340
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Tidskriftsartikel (refereegranskat)abstract
- Objective Degarelix (FE200486) is a new GnRH-receptor antagonist intended for the treatment of prostate cancer. The objective of the present analysis was to evaluate the pharmacokinetics of degarelix after subcutaneous (s.c.) and intra-muscular (i.m.) administration to male beagle dogs, and to determine the influence of the different dosing conditions on the absorption profile of degarelix. Methods Degarelix was administered to 27 dogs and plasma concentrations were measured. The dosing conditions varied with respect to route (s.c. or i.m.), dose (0.25–1.5 mg/kg), solution strength (1.25–40 mg/ml) and volume administered (0.15–2.9 ml). Data were analysed by use of non-linear mixed effect modelling to characterize the pharmacokinetics, in particular the relationship between dosing conditions and rate, and extent of absorption. Results After s.c. and i.m. administration of degarelix, the plasma concentration versus time profile was best described by applying a two-compartment model, with two input functions: a fast first-order input function to describe the rapid initial increase in the plasma concentration levels, and a slow first-order input function to describe the prolonged absorption profile of degarelix. Intra-muscular as opposed to s.c. administration led to a more rapid absorption of degarelix, reaching a mean maximum concentration of 64 and 31 ng/ml roughly 2.0 and 3.7 h after administration, respectively. The slow absorption half-life was found to be 268 h (∼11 days). The relative fraction absorbedwas found to vary with the concentration of the dosing solution. The present analysis suggested that the absorbed fractionwas reduced by approximately 50% when the concentration in dosing solution was increased from 1.25 to 40 mg/ml. The rate of the initial absorption component was also dependent on the concentration in the dosing solution, with slower absorption at higher concentrations. Conclusion Through varying the dosing conditions and by applying a joint analysis of all data, the important factors determining the complex absorption of degarelix could be described.
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| 2. |
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| 3. |
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| 4. |
- Davila, M. E., et al.
(författare)
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Surface phase transitions at metal-semiconductor interfaces : a revisit is needed
- 2004
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Ingår i: Applied Surface Science. - : Elsevier BV. - 0169-4332 .- 1873-5584. ; 234:04-jan, s. 274-285
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Tidskriftsartikel (refereegranskat)abstract
- In this article, we review some of the most recent progress and understanding in the low temperature surface phase transitions at prototypical metal-semiconductor interfaces. We essentially focus on quantitative surface structural information obtained by using a significant variety of specialised techniques for the individual phases of a model system, namely, tin on Ge(1 1 1) substrates. The strengths and limitations of the structural results obtained by using scanning tunnelling microscopy, photoelectron diffraction and surface X-ray diffraction are discussed in relation to their support with respect to possible mechanisms recently invoked in the literature as being at the origin of the phase transition. These investigations show that a large progress has been made in this field, taking into account the very valuable experimental and theoretical contributions provided by different groups. There remain, however, essential unresolved problems, which will be analysed in the light of the limitations of these structural methods and the difficulty presented by the complex adsorbate systems studied.
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| 5. |
- Eriksson, Ulf G, et al.
(författare)
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Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran : a population model analysis
- 2003
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Ingår i: Clinical Pharmacokinetics. - 0312-5963 .- 1179-1926. ; 42:7, s. 687-701
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Forskningsöversikt (refereegranskat)abstract
- OBJECTIVE: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined. DESIGN AND METHODS: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model. RESULTS: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT. CONCLUSIONS: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.
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| 6. |
- Friberg, Lena E, et al.
(författare)
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Mechanistic models for myelosuppression
- 2003
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Ingår i: Investigational new drugs. - 0167-6997 .- 1573-0646. ; 21:2, s. 183-194
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Tidskriftsartikel (refereegranskat)abstract
- As myelosuppression is the dose-limiting toxicity for most chemotherapeutic drugs, modelers attempt to find relationships between drug and toxicity to optimize treatment. Mechanistic models, i.e. models based on physiology and pharmacology, are preferable over empirical models, as prior information can be utilized and as they generally are more reliable for extrapolations. To account for different dosing-regimens and possible schedule-dependent effects, the whole concentration-time profile should be used as input into the pharmacokinetic-pharmacodynamic model. It is also of importance to model the whole time course of myelosuppression to be able to predict both the degree and duration of toxicity as well as consecutive courses of therapy. A handful of (semi)-mechanistic pharmacokinetic-pharmacodynamic models with the above properties have been developed and are reviewed. Ideally, a model of myelosuppression should separate drug-specific parameters from system related parameters to be applicable across drugs and useful under different clinical settings. Introduction of mechanistic models of myelosuppression in the design and evaluation of clinical trials can guide in the decision of optimal sampling times, contribute to knowledge of optimal doses and treatment regimens at an earlier time point and identify sub-groups of patients at a high risk of myelosuppression.
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| 7. |
- Friberg, Lena E., et al.
(författare)
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Model of Chemotherapy-Induced Myelosuppression With Parameter Consistency Across Drugs
- 2002
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 20:24, s. 4713-4721
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To develop a semimechanistic pharmacokinetic-pharmacodynamic model describing chemotherapy-induced myelosuppression through drug-specific parameters and system-related parameters, which are common to all drugs. PATIENTS AND METHODS: Patient leukocyte and neutrophil data after administration of docetaxel, paclitaxel, and etoposide were used to develop the model, which was also applied to myelosuppression data from 2'-deoxy-2'-methylidenecytidine (DMDC), irinotecan (CPT-11), and vinflunine administrations. The model consisted of a proliferating compartment that was sensitive to drugs, three transit compartments that represented maturation, and a compartment of circulating blood cells. Three system-related parameters were estimated: baseline, mean transit time, and a feedback parameter. Drug concentration-time profiles affected the proliferation of sensitive cells by either an inhibitory linear model or an inhibitory E(max) model. To evaluate the model, system-related parameters were fixed to the same values for all drugs, which were based on the results from the estimations, and only drug-specific parameters were estimated. All modeling was performed using NONMEM software. RESULTS: For all investigated drugs, the model successfully described myelosuppression. Consecutive courses and different schedules of administration were also well characterized. Similar system-related parameter estimates were obtained for the different drugs and also for leukocytes compared with neutrophils. In addition, when system-related parameters were fixed, the model well characterized chemotherapy-induced myelosuppression for the different drugs. CONCLUSION: This model predicted myelosuppression after administration of one of several different chemotherapeutic drugs. In addition, with fixed system-related parameters to proposed values, and only drug-related parameters estimated, myelosuppression can be predicted. We propose that this model can be a useful tool in the development of anticancer drugs and therapies.
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| 8. |
- Grehk, T. M., et al.
(författare)
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Li-induced phase transition from the Ge(111)3X1 : Li surface reconstruction to the Ge(111)root 3X root 3 : Li lithium germanide
- 2000
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 61:7, s. 4963-4967
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated the Li-induced phase transition from the Ge(111)3X1:Li to the Ge(111)root 3X root 3:Li reconstruction with photoemission. The Ge(111)3X1:Li reconstruction can be described as parallel rows of Ge atoms separated by single rows of Li atoms. The Ge(111)root 3X root 3:Li reconstruction, on the other hands, has to be described in terms of a Li-germanide phase extending over at least two atomic layers.
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| 9. |
- Göthelid, Mats, et al.
(författare)
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An ordered layer of molecular iodine on Ge(100) 2x1
- 2004
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Ingår i: Surface Science. - : Elsevier BV. - 0039-6028 .- 1879-2758. ; 556:03-feb, s. 203-212
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Tidskriftsartikel (refereegranskat)abstract
- Adsorption of iodine on the Ge(1 0 0) (2 x 1) surface has been investigated by core level and valence band photoelectron spectroscopy and scanning tunnelling microscopy. Iodine binds to dimer atom dangling bonds without disrupting the dimers at all coverages. At saturation a c(2 x 2) ordered layer of molecular iodine develops on top of a (2 x 2) ordered structure of atomic iodine binding to asymmetric Ge-dimers. Annealing destroys the molecular character and etches the surface by Ge dimer bond breaking and attachment of additional iodine to these Ge atoms to form GeI2, which desorbs from the surface.
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| 10. |
- Hassan, Saadia Bashir, et al.
(författare)
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A hollow fiber model for in vitro studies of cytotoxic compounds : Activity of the cyanoguanidine CHS 828
- 2001
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 12:1, s. 33-42
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Tidskriftsartikel (refereegranskat)abstract
- The hollow fiber assay is currently used as an in vivo model for anticancer drug screening in nude mice, but it can also be used as an in vitro model. In the current study, an in vitro hollow fiber model was used to study the effect and mode of induced cell death of a new cyanoguanidine, CHS 828. Human leukemia, adenocarcinoma and lymphoma cell lines as well as primary cultures of human tumor cells from patients with chronic lymphocytic leukemia (CLL) and ovarian cancer (OC) and normal human lymphocytes were cultured in semipermeable hollow fibers. The fibers were incubated for 3 or 14 days prior to CHS 828 exposure for 72 h, followed by determination of living cell density by MTT staining. For cell morphology, using harvested cultures on cytospin slides had technical advantages compared to using paraffin sections of the formalin-fixed fibers. CHS 828 showed higher antitumor activity on CLL and normal human lymphocyte cultures compared to OC cultures, and cell lines cultured 3 days were more sensitive than those cultured 14 days. Morphological examination of CHS 828-treated cultures revealed a mixture of apoptosis and necrosis.
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| 11. |
- Hassan, Saadia Bashir, 1959-
(författare)
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Methods for Preclinical Evaluation of Cytotoxic Drugs : With Special Reference to the Cyanoguanidine CHS 828 and Hollow Fiber Method
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The novel cyanoguanidine CHS 828 has shown promising antitumor activity in many in vitro and in vivo studies. The long-term 14 days in vitro hollow fiber cultures, where tumor cells from different tumor cell lines were cultured inside semipermeable fibers, were more resistant to CHS 828 and other cytotoxic drugs than the shorter-term 3 days cultures. CHS 828 was generally more effective against haematological than solid tumor cells from both cell lines and patients samples. In vivo, the hollow fibers were implanted into immunocompetent rats and the pharmacokinetics, tumor response and/or toxicity (pharmacodynamics) of CHS 828 were successfully assayed. CHS 828 showed higher activity in this model when a more protracted schedule was used. The quantitative relationships between dose, plasma concentration and response (PK/PD model) developed for CHS 828 explained this phenomenon partly by dose-dependent fraction absorbed and partly by a schedule-dependent pharmacodynamic effect.Modelling of the in vitro CHS 828 and standard cytotoxic drugs concentration-time effect data in different tumor cell types and characterization of pattern of change of the potency and the slope of the concentration-time effect curves were performed. The results suggest two different mechanisms of action for CHS 828 and that CHS 828 cytotoxicity may depend on the schedule used.The NF-kB pathway that regulates the transcription of anti-apoptotic genes proved to be inhibited by CHS 828 in different tumor cell lines and the inhibition was correlated to the cell death induced by this agent. CHS 828 did not seem to induce the NF-kB inhibition by affecting the proteasome activity. The in vitro and in vivo hollow fiber methods were also used successfully to evaluate the new paclitaxel formulation, Pacliex. Pacliex had a similar activity to that of the clinically used formulation Taxol®.
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| 12. |
- Hassan, Saadia Bashir, et al.
(författare)
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Model for time dependency of the cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action
- 2001
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 0022-3565 .- 1521-0103. ; 299:3, s. 1140-1147
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Tidskriftsartikel (refereegranskat)abstract
- CHS 828 is a novel drug belonging to the cyanoguanidines. It has shown promising anticancer activity in many preclinical systems and is currently in early clinical trials. Our aim in this study was to assess the growth inhibitory effect of CHS 828 in comparison with paclitaxel, etoposide, and topotecan as a function of concentration and time. U937 GTB, RPMI 8226/S, MDA 231, primary cells from chronic lymphocytic leukemia, and normal mononuclear cells were exposed to CHS 828 and U937 GTB cells were exposed to paclitaxel, etoposide, and topotecan in 18 concentrations for times ranging from 1 to 72 h. Cell survival was measured after 72-h incubation by using the fluorometric microculture cytotoxicity assay. Nonlinear mixed effect modeling was used to model the concentration-effect curves with a modified Hill equation. Patterns of change of drug potency (IC(50)), slope of the concentration-effect curves, and plateau with time were studied. The log IC(50) for CHS 828 decreased with log time in a sigmoid manner for all cell types tested. Although very steep at short and long incubation, the concentration-effect curves became shallow at intermediate times. The log IC(50) for etoposide and topotecan was decreased with log time in a sigmoid manner. The log IC(50) for paclitaxel decreased linearly with log time. The information obtained from modeling the cytotoxic effect of CHS 828 and changes of IC(50) and slope parameters with exposure time suggests a heterogeneous cell response to CHS 828. This could indicate two distinct mechanisms of induction of cell death.
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| 13. |
- Henningsson, Anja, et al.
(författare)
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Mechanism-based pharmacokinetic model for paclitaxel
- 2001
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 19:20, s. 4065-4073
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE To create a model based on known mechanisms of paclitaxel distribution that could describe the pharmacokinetics (PK) of total and unbound plasma concentrations, as well as blood concentrations. In addition, to investigate the relationship between exposure, based on unbound and total concentrations, and neutropenia. PATIENTS AND METHODS Paclitaxel and Cremophor EL (CrEL) concentrations were obtained from 23 female and three male patients (50 courses in total) with different cancer types that received paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) (135 to 225 mg/m(2)) as 3- or 24-hour intravenous infusions. Seven of the patients received combination therapy with doxorubicin or cisplatin. The population PK model was built to fit three types of data simultaneously: unbound, total plasma, and blood concentrations. The area under the curve, threshold, and general models were used to relate neutrophil survival fraction from 19 patients (29 courses in total) to exposure based on unbound and total plasma concentration, respectively. RESULTS The PK model included a linear three-compartment model for unbound concentration, binding directly proportional to CrEL, linear and nonlinear binding to plasma proteins, and linear and nonlinear binding to blood cells. The threshold model best described the PK/pharmacodynamic (PD) relationship for total concentration. No distinction could be made between the models for unbound drug. CONCLUSION Earlier PK models for paclitaxel have been empirical. This study shows that a mechanistic model can be used to describe the nonlinear PK of paclitaxel. There is an indication that the PK/PD relationship is not the same for unbound and total plasma concentrations.
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| 14. |
- Henningsson, Anja, et al.
(författare)
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Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients
- 2003
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Ingår i: European Journal of Cancer. - 0959-8049 .- 1879-0852. ; 39:8, s. 1105-1114
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to validate and further develop a mechanism-based population pharmacokinetic model for paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ, USA) based on the knowledge of Cremophor EL (CrEL) micelle entrapment and to evaluate the exposure/toxicity relationships. Paclitaxel (total and unbound) and CrEL concentrations were obtained according to a sparse sampling scheme with on average only 3.5 samples per course from 45 patients with solid tumours who received 3-hour infusions of paclitaxel (final dose range 112-233 mg/m(2)). The present data were predicted well by the mechanism-based model. In addition, bilirubin and body size were found to be significant as covariates. A change in body surface area (BSA) of 0.1 m(2) typically caused a change in clearance (CL) of 22.3 l/h and an increase in bilirubin of 10 microM typically caused a decrease in CL of 41 l/h. Toxicity was best described by a threshold model. In conclusion, even with a sparse sampling scheme, the same mechanism-based binding components as in the previously developed model could be identified. Once the CrEL and total paclitaxel plasma concentrations are known, the unbound concentrations, which are more closely related to the haematological toxicity, can be predicted.
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| 15. |
- Hirschauer, B., et al.
(författare)
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Oxidation of Ce on Si(111) studied by high-resolution photoelectron spectroscopy
- 2000
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Ingår i: Surface Science. - 0039-6028 .- 1879-2758. ; 464:03-feb, s. 117-122
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Tidskriftsartikel (refereegranskat)abstract
- The Si(lll)-Ce (2x2) surface was studied by photoelectron spectroscopy during oxidation and annealing. Detailed analysis of the Si 2p core-level spectra and the Ce valence band levels shows that Ce is first oxidised and then promotes oxidation of Si at room temperature by improving the oxygen uptake of the surface. Initially, no oxidation of Si can be recorded, but at exposures of 3 L O-2 or more, SiOx and higher silicon oxides are formed. After annealing to 750 degreesC, a temperature that is generally used to oxidise Si, almost all O leaves the surface. At 1045 degreesC, the Si 2p and the Ce valence band spectra of the sample show almost the same shape as for the original Si(lll)-Ce 2x2 surface. This means that oxidation/reduction of the Si(lll)-Ce 2x2 surface is reversible.
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| 16. |
- Hornestam, Björn, et al.
(författare)
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Intravenously administered digoxin in patients with acute atrial fibrillation : a population pharmacokinetic/pharmacodynamic analysis based on the Digitalis in Acute Atrial Fibrillation trial
- 2003
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 58:11, s. 747-755
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Atrial fibrillation is commonly treated with intravenously administered digoxin. The main objective of this study was to investigate the relationship between plasma concentration of digoxin and heart rate. SUBJECTS AND METHODS: Plasma concentrations of digoxin were analysed in 105 patients allocated to digoxin therapy in the Digitalis in Acute Atrial Fibrillation (DAAF) trial. A pharmacokinetic/pharmacodynamic (PK/PD) model for the relationship among digoxin dose, plasma concentration and heart rate in patients remaining in atrial fibrillation was constructed using non-linear, mixed-effect modelling. One hundred and twenty-two placebo-treated patients were included as a control group. In 56 patients, one late sample at 16 h after the first dose of digoxin was obtained while in 49 patients an early sample at 0.25-0.5 h and a late sample 16 h after the first dose were obtained. Heart rate was measured at 0, 2, 6, 12 and 16 h after inclusion, with data from 98, 89, 67, 56 and 53 patients available at each time point, respectively. RESULTS: A two-compartment model best described the time course of digoxin concentrations in plasma. Digoxin and creatinine clearance correlated strongly and mean plasma concentration of digoxin at 16 h was within recommended levels (1.6+/-1.0 nM). The decrease in heart rate in placebo-treated patients was, on average, 0.5 beats/min (bpm) per hour. In patients on digoxin, a linear relationship between the estimated digoxin concentration at the effect site and the drop-in heart rate was found. The half-life for the digoxin distribution to the effect compartment was approximately 3.8 h. The degree of reduction was related to the initial heart rate and patients with higher heart rate had a more pronounced decrease. The model predicted that a digoxin concentration of 1 nM at the effect site reduces heart rate by 9.4%. CONCLUSION: A PK/PD model for the relationship between the plasma concentration of digoxin, the estimated concentration at the effect site and the reduction in heart rate during atrial fibrillation could be defined using a population pharmacokinetic approach. Our data indicate that a more aggressive dosing regimen of digoxin may be more effective in terms of heart rate reduction.
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| 17. |
- Hovstadius, Peter, et al.
(författare)
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A Phase I Study of CHS 828 in Patients with Solid Tumor Malignancy
- 2002
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 8:9, s. 2843-2850
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Tidskriftsartikel (refereegranskat)abstract
- CHS 828 is a cyanoguanidine, which has demonstrated potent antitumor activity in preclinical tumor models. The activity of CHS 828 in vitro showed only low to moderate correlation to other antineoplastic agents suggesting a unique mechanism of action. Ten females and 6 males (median age 58 years) with solid tumors refractory to standard therapy were included in this Phase I study. The study drug was administered to fasting patients as a single oral dose on days 1–5 of each treatment cycle. Patients received one to six cycles of treatment. The doses ranged from 30 mg to 200 mg (total dose within a cycle). Hematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Nonhematological toxicity most frequently consisted of nausea, vomiting, diarrhea, fatigue, and localized genital mucositis. The dose-limiting toxicities were thrombocytopenia, thrombosis, esophagitis, diarrhea, and constipation. The recommended Phase II dose of CHS 828 was 20 mg once daily for 5 days in cycles of 28 days duration. The extent of systemic exposure of CHS 828 across patients was approximately dose proportional. The time at which the highest drug concentration occurs was 2.2 ± 1.3 h and half-life was 2.1 ± 0.52 h (mean ± SD). Large intra- and interindividual variation in dose level-adjusted maximum plasma concentration and the area under the curve from time 0 h to infinity were observed. There was an apparent inverse relationship between systemic exposure of CHS 828, and thrombocyte and lymphocyte nadir levels. No objective tumor responses were observed, and 7 patients showed stable disease after two courses of therapy.
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| 18. |
- Janin, Emmanuelle, et al.
(författare)
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Adsorption and bonding of propene and 2-butenal on Pt(111)
- 2001
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Ingår i: Surface Science. - 0039-6028 .- 1879-2758. ; 482, s. 83-89
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Tidskriftsartikel (refereegranskat)abstract
- The adsorption of propene and 2-butenal on the Pt(1 1 1) surface has been studied by high resolution photoelectron spectroscopy, both in the mono-and multi-layer regime. The results obtained indicate an involvement of both aliphatic and carbonyl groups in the bonding of 2-butenal with the platinum surface in the sub-monolayer regime.
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| 19. |
- Janin, E., et al.
(författare)
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Bridge-bonded atomic oxygen on Pt(110)
- 2000
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Ingår i: Physical Review B Condensed Matter. - 0163-1829 .- 1095-3795. ; 61:19, s. 13144-13149
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Tidskriftsartikel (refereegranskat)abstract
- We use hybrid density-functional theory (DFT) and scanning tunneling microscopy (STM) to study oxygen adsorption on the Pt(110) surface. In the STM images oxygen appear as bright protrusions on the ridges of the missing row reconstructed surface. DFT calculations of binding energies for atomic oxygen on a bridge site shows a clear preference over hollow sites.
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| 20. |
- Janin, E., et al.
(författare)
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Corrosive adsorption of Sn on the Pt(110)(1 x 2) surface
- 2002
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Ingår i: Surface Science. - 0039-6028 .- 1879-2758. ; 515:03-feb, s. 462-470
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Tidskriftsartikel (refereegranskat)abstract
- Room temperature deposition of Sn on the Pt(110)(1 x 2) surface has been studied by scanning tunnelling microscopy and core level photoelectron spectroscopy. At low coverage Sri is found in three different configurations; as mobile adatoms in the valley of the missing-row reconstruction, as 1D-Pt-Sn-Pt- alloy chains forming local Pt3Sn(110)2 x 2 regions and finally as 3D alloy islands. At higher coverage these islands form a platinum rich alloy film, which is dissolved in the crystal upon annealing to 600 degreesC.
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| 21. |
- Janin, E., et al.
(författare)
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Formation of two-dimensional graphite islands on the Pt(110)(1x2) surface
- 2000
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Ingår i: Applied Surface Science. - 0169-4332 .- 1873-5584. ; 162, s. 184-189
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Tidskriftsartikel (refereegranskat)abstract
- The formation of thin carbon overlayers at temperatures above 600 degrees C has been studied on the Pt(110)(1 X 2) surface by Scanning Tunneling Microscopy (STM), PES and Low-Energy Electron Diffraction (LEED). Their graphitic character is evidenced through the binding energy of the Cls core-level, the LEED pattern observed and the atomic structure resolved on the islands. The orientation of the graphite layers is determined to be C < 1010 > parallel to the Pt[110] direction. Their thickness and the nature of the substrate are discussed below.
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| 22. |
- Jonsson, Elin, et al.
(författare)
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Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats
- 2000
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 46:6, s. 493-500
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Based on the previously published hollow-fibre assay mainly used for early in vivo anticancer drug screening, we wanted to develop an extended hollow-fibre model in which antitumour activity, haematological toxicity and pharmacokinetics could be studied in the same animal. METHOD The breast cancer cell lines MDA-MB-231 and MCF-7 were cultured in semipermeable hollow fibres. The fibres were implanted subcutaneously into immunocompetent male Sprague Dawley rats, and the rats were treated with 5-fluorouracil (5-FU, 125 mg/kg), epirubicin (EPI, 10 mg/kg) or cyclophosphamide (CP, 120 mg/kg) intraperitoneally, the new cyanoguanidine CHS 828 (375 mg/kg or 75 mg/kg x 5) orally, or vehicle only. After 6 days the fibres were retrieved and the cell density was evaluated. Haematological parameters were monitored and two to four samples per animal were drawn to determine the pharmacokinetic parameters in NONMEM. RESULTS Drug treatment had generally low effects on the tumour cells. Of the standard drugs (5-FU, EPI and CP), only CP exerted a statistically significant antiproliferative effect. CHS 828 had only a minor effect as a single dose, but divided into five daily doses had a pronounced effect on both cell lines. 5-FU, EPI and CP all caused a marked decrease in leucocytes, platelets and haemoglobin, while CHS 828 did not seem to affect these parameters. The pharmacokinetics of 5-FU and EPI were in accordance with previously established pharmacokinetic models. The pharmacokinetics of CP and CHS 828 were both described by one-compartment models. CONCLUSIONS This study illustrates the possibility of measuring antitumour effect, haematological toxicity and pharmacokinetics in the same animal using the hollow-fibre model.
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| 23. |
- Jonsson, E Niclas, et al.
(författare)
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Population pharmacokinetics of levosimendan in patients with congestive heart failure
- 2003
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 55:6, s. 544-551
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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.
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| 24. |
- Jönsson, Siv, et al.
(författare)
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A rational approach for selection of optimal covariate-based dosing strategies
- 2003
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 73:1, s. 7-19
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: At present, there is no rational approach for choosing a dosing strategy for individualization based on a covariate. An approach to use in establishment of an a priori dosing strategy for individualization is presented. Factors influencing the choice of such a dosing strategy are identified. METHODS: The approach requires definition of the following: target variable, seriousness of deviations from the target (ie, risk function), population model, covariate distributions, and constraints. Minimizing the total risk yields an optimal dosing strategy, estimated as dose sizes for different subpopulations and covariate cutoff values at which doses are increased or decreased. The method was illustrated with the use of simulated and real drug examples for the situation in which clearance is related to creatinine clearance. RESULTS: The estimated optimal cutoff(s) paralleled the median creatinine clearance in the population. The extent of variability in clearance explained by creatinine clearance was the main factor influencing the optimal ratios between adjacent dose sizes. An optimal dosing strategy was possible to estimate for the real drug. CONCLUSIONS: The method is simple to perform, although one difficulty lies in defining the target variable and risk function. Our results imply that commonly used constraints in dosing strategies based on renal function (ie, dose ratio of 2 and predetermined cutoffs) are nonoptimal in the sense we propose. Because an optimal dosing strategy may not be practical to use, the therapeutic cost that would result with any constraint can be assessed by comparison of the outcome after the desired and the optimal strategy.
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| 25. |
- Jönsson, Siv, et al.
(författare)
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Estimating bias in population parameters for some models for repeated measures ordinal data using NONMEM or NLMIXED
- 2004
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - 1567-567X .- 1573-8744. ; 31:4, s. 299-320
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Tidskriftsartikel (refereegranskat)abstract
- The application of proportional odds models to ordered categorical data using the mixed-effects modeling approach has become more frequently reported within the pharmacokinetic/pharmacodynamic area during the last decade. The aim of this paper was to investigate the bias in parameter estimates, when models for ordered categorical data were estimated using methods employing different approximations of the likelihood integral; the Laplacian approximation in NONMEM (without and with the centering option) and NLMIXED, and the Gaussian quadrature approximations in NLMIXED. In particular, we have focused on situations with non-even distributions of the response categories and the impact of interpatient variability. This is a Monte Carlo simulation study where original data sets were derived from a known model and fixed study design. The simulated response was a four-category variable on the ordinal scale with categories 0, 1, 2 and 3. The model used for simulation was fitted to each data set for assessment of bias. Also, simulations of new data based on estimated population parameters were performed to evaluate the usefulness of the estimated model. For the conditions tested, Gaussian quadrature performed without appreciable bias in parameter estimates. However, markedly biased parameter estimates were obtained using the Laplacian estimation method without the centering option, in particular when distributions of observations between response categories were skewed and when the interpatient variability was moderate to large. Simulations under the model could not mimic the original data when bias was present, but resulted in overestimation of rare events. The bias was considerably reduced when the centering option in NONMEM was used. The cause for the biased estimates appears to be related to the conditioning on uninformative and uncertain empirical Bayes estimate of interindividual random effects during the estimation, in conjunction with the normality assumption.
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