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| 2. |
- Luo, Jinghui, et al.
(författare)
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Cellular Polyamines Promote Amyloid-Beta (A beta) Peptide Fibrillation and Modulate the Aggregation Pathways
- 2013
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 4:3, s. 454-462
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Tidskriftsartikel (refereegranskat)abstract
- The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (A beta) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric A beta(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 mu M spermine (normal intracellular concentration is similar to 1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine and putrescine additions yielded similar but weaker effects. CD measurements demonstrated that the three polyamines induce different aggregation pathways, involving different forms of induced secondary structure. This is supported by AFM images showing that the three polyamines induce A beta(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of A beta peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.
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| 4. |
- Brussee, Janneke M., et al.
(författare)
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Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach
- 2018
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Ingår i: Pharmaceutical research. - : Springer. - 0724-8741 .- 1573-904X. ; 35:9
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates. Methods Pharmacokinetic (PK) data of midazolam and 1-OH-midazolam from 264 post-operative children 1-18 years of age after oral administration were analyzed using a physiological population PK. modelling approach. In the model, consisting of physiological compartments representing the gastro-intestinal tract and liver,intrinsic intestinal and hepatic clearances were estimated to derive values for bioavailability and plasma clearance. Results The whole-organ intrinsic clearance in the gut wall and liver were found to increase with body weight, with a 105 (95% confidence interval (CI): 5-405) times lower intrinsic gut wall clearance than the intrinsic hepatic dearance (i.e. 5.08 L/h (relative standard error (RSE) 10%) versus 527 L/h (RSE 7%) for a 16 kg individual, respectively). When expressed per gram of organ, intrinsic clearance increases with increasing body weight in the gut wall, but decreases in the liver, indicating that CYP3A-mediated intrinsic clearance and local bioavailability in the gut wall and liver do not change with age in parallel. The resulting total bioavailability was found to be age-independent with a median of 20.8% in children (95%CI: 3.8-50.0%). Conclusion In conclusion, the intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance in children from 1 to 18 years of age, and contributes less to the overall first-pass metabolism compared to adults.
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| 5. |
- Brussee, Janneke M., et al.
(författare)
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First-Pass CYP3A-Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates
- 2018
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Ingår i: CPT. - : WILEY. - 2163-8306. ; 7:6, s. 374-383
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Tidskriftsartikel (refereegranskat)abstract
- To predict first-pass and systemic cytochrome P450 (CYP) 3A-mediated metabolism of midazolam in preterm neonates, a physiological population pharmacokinetic model was developed describing intestinal and hepatic midazolam clearance in preterm infants. On the basis of midazolam and 1-OH-midazolam concentrations from 37 preterm neonates (gestational age 26-34 weeks) receiving midazolam orally and/or via a 30-minute intravenous infusion, intrinsic clearance in the gut wall and liver were found to be very low, with lower values in the gut wall (0.0196 and 6.7 L/h, respectively). This results in a highly variable and high total oral bioavailability of 92.1% (range, 67-95%) in preterm neonates, whereas this is around 30% in adults. This approach in which intestinal and hepatic clearance were separately estimated shows that the high bioavailability in preterm neonates is explained by, likely age-related, low CYP3A activity in the liver and even lower CYP3A activity in the gut wall.
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- van Eijk, Maarten, et al.
(författare)
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Development of a population pharmacokinetic/pharmacodynamic model for various oral paclitaxel formulations co-administered with ritonavir and thrombospondin-1 based on data from early phase clinical studies.
- 2022
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer. - 0344-5704 .- 1432-0843. ; 90:1, s. 71-82
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Orally administered paclitaxel offers increased patient convenience while providing a method to prolong exposure without long continuous, or repeated, intravenous infusions. The oral bioavailability of paclitaxel is improved through co-administration with ritonavir and application of a suitable pharmaceutical formulation, which addresses the dissolution-limited absorption of paclitaxel. We aimed to characterize the pharmacokinetics of different paclitaxel formulations, co-administered with ritonavir, and to investigate a pharmacodynamic relationship between low-dose metronomic (LDM) treatment with oral paclitaxel and the anti-angiogenic marker thrombospondin-1 (TSP-1).METHODS: Fifty-eight patients treated with different oral paclitaxel formulations were included for pharmacokinetic analysis. Pharmacodynamic data was available for 36 patients. All population pharmacokinetic/pharmacodynamic modelling was performed using non-linear mixed-effects modelling.RESULTS: A pharmacokinetic model consisting of gut, liver, central, and peripheral compartments was developed for paclitaxel. The gastrointestinal absorption rate was modelled with a Weibull function. Relative gut bioavailabilities of the tablet and capsule formulations, as fractions of the gut bioavailability of the drinking solution, were estimated to be 0.97 (95%CI: 0.67-1.33) and 0.46 (95%CI: 0.34-0.61), respectively. The pharmacokinetic/pharmacodynamic relationship between paclitaxel and TSP-1 was modelled using a turnover model with paclitaxel plasma concentrations driving an increase in TSP-1 formation rate following an Emax relationship with an EC50 of 284 ng/mL (95%CI: 122-724).CONCLUSION: The developed pharmacokinetic model adequately described the paclitaxel plasma concentrations for the different oral formulations co-administered with ritonavir. This model, and the established pharmacokinetic/pharmacodynamic relationship with TSP-1, may facilitate future development of oral paclitaxel.
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- Yu, Huixin, et al.
(författare)
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Quantification of the pharmacokinetic-toxicodynamic relationship of oral docetaxel co-administered with ritonavir.
- 2020
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Ingår i: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 38:5, s. 1526-1532
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Oral formulations of docetaxel have successfully been developed as an alternative for intravenous administration. Co-administration with the enzyme inhibitor ritonavir boosts the docetaxel plasma exposure. In dose-escalation trials, the maximum tolerated doses for two different dosing regimens were established and dose-limiting toxicities (DLTs) were recorded. The aim of current analysis was to develop a pharmacokinetic (PK)-toxicodynamic (TOX) model to quantify the relationship between docetaxel plasma exposure and DLTs. Methods A total of 85 patients was included in the current analysis, 18 patients showed a DLT in the four-week observation period. A PK-TOX model was developed and simulations based on the PK-TOX model were performed. Results The final PK-TOX model was characterized by an effect compartment representing the toxic effect of docetaxel, which was linked to the probability of developing a DLT. Simulations of once-weekly, once-daily 60 mg and once-weekly, twice-daily 30 mg followed by 20 mg of oral docetaxel suggested that 14% and 34% of patients, respectively, would have a probability >25% to develop a DLT in a four-week period. Conclusions A PK-TOX model was successfully developed. This model can be used to evaluate the probability of developing a DLT following treatment with oral docetaxel and ritonavir in different dosing regimens.
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