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| 2. |
- Bällgren, Frida, et al.
(författare)
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Active Uptake of Oxycodone at Both the Blood-Cerebrospinal Fluid Barrier and The Blood-Brain Barrier without Sex Differences : A Rat Microdialysis Study
- 2023
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Ingår i: Pharmaceutical research. - : Springer Nature. - 0724-8741 .- 1573-904X. ; 40, s. 2715-2730
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Tidskriftsartikel (refereegranskat)abstract
- Background: Oxycodone active uptake across the blood-brain barrier (BBB) is associated with the putative proton-coupled organic cation (H+/OC) antiporter system. Yet, the activity of this system at the blood-cerebrospinal fluid barrier (BCSFB) is not fully understood. Additionally, sex differences in systemic pharmacokinetics and pharmacodynamics of oxycodone has been reported, but whether the previous observations involve sex differences in the function of the H+/OC antiporter system remain unknown. The objective of this study was, therefore, to investigate the extent of oxycodone transport across the BBB and the BCSFB in female and male Sprague-Dawley rats using microdialysis.Methods: Microdialysis probes were implanted in the blood and two of the following brain locations: striatum and lateral ventricle or cisterna magna. Oxycodone was administered as an intravenous infusion, and dialysate, blood and brain were collected. Unbound partition coefficients (Kp,uu) were calculated to understand the extent of oxycodone transport across the blood-brain barriers. Non-compartmental analysis was conducted using Phoenix 64 WinNonlin. GraphPad Prism version 9.0.0 was used to perform t-tests, one-way and two-way analysis of variance followed by Tukey's or Sidak's multiple comparison tests. Differences were considered significant at p < 0.05.Results: The extent of transport at the BBB measured in striatum was 4.44 ± 1.02 (Kp,uu,STR), in the lateral ventricle 3.41 ± 0.74 (K-p,K-uu,K-LV) and in cisterna magna 2.68 ± 1.01 (Kp,Kuu,KCM). These Kp,uu values indicate that the extent of oxycodone transport is significantly lower at the BCSFB compared with that at the BBB, but still confirm the presence of active uptake at both blood-brain interfaces. No significant sex differences were observed in neither the extent of oxycodone delivery to the brain, nor in the systemic pharmacokinetics of oxycodone.Conclusions: The findings clearly show that active uptake is present at both the BCSFB and the BBB. Despite some underestimation of the extent of oxycodone delivery to the brain, CSF may be an acceptable surrogate of brain ISF for oxycodone, and potentially also other drugs actively transported into the brain via the H+/OC antiporter system.
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| 3. |
- Chen, Eugene C., et al.
(författare)
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High Throughput Screening of a Prescription Drug Library for Inhibitors of Organic Cation Transporter 3, OCT3
- 2022
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Ingår i: Pharmaceutical research. - : Springer. - 0724-8741 .- 1573-904X. ; 39:7, s. 1599-1613
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Tidskriftsartikel (refereegranskat)abstract
- Introduction The organic cation transporter 3 (OCT3, SLC22A3) is ubiquitously expressed and interacts with a wide array of compounds including endogenous molecules, environmental toxins and prescription drugs. Understudied as a determinant of pharmacokinetics and pharmacodynamics, OCT3 has the potential to be a major determinant of drug absorption and disposition and to be a target for drug-drug interactions (DDIs).Goal The goal of the current study was to identify prescription drug inhibitors of OCT3.Methods We screened a compound library consisting of 2556 prescription drugs, bioactive molecules, and natural products using a high throughput assay in HEK-293 cells stably expressing OCT3.Results We identified 210 compounds that at 20 mu M inhibit 50% or more of OCT3-mediated uptake of 4-Di-1-ASP (2 mu M). Of these, nine were predicted to inhibit the transporter at clinically relevant unbound plasma concentrations. A Structure-Activity Relationship (SAR) model included molecular descriptors that could discriminate between inhibitors and non-inhibitors of OCT3 and was used to identify additional OCT3 inhibitors. Proteomics of human brain microvessels (BMVs) indicated that OCT3 is the highest expressed OCT in the human blood-brain barrier (BBB).Conclusions This study represents the largest screen to identify prescription drug inhibitors of OCT3. Several are sufficiently potent to inhibit the transporter at therapeutic unbound plasma levels, potentially leading to DDIs or off-target pharmacologic effects.
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| 4. |
- Faresjö, Rebecca, et al.
(författare)
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Transferrin Receptor Binding BBB-Shuttle Facilitates Brain Delivery of Anti-Aβ-Affibodies
- 2022
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Ingår i: Pharmaceutical research. - : Springer Nature. - 0724-8741 .- 1573-904X. ; 39:7, s. 1509-1521
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Tidskriftsartikel (refereegranskat)abstract
- Affibodies targeting amyloid-beta (Aβ) could potentially be used as therapeutic and diagnostic agents in Alzheimer’s disease (AD). Affibodies display suitable characteristics for imaging applications such as high stability and a short biological half-life. The aim of this study was to explore brain delivery and retention of Aβ protofibril-targeted affibodies in wild-type (WT) and AD transgenic mice and to evaluate their potential as imaging agents. Two affibodies, Z5 and Z1, were fused with the blood–brain barrier (BBB) shuttle single-chain variable fragment scFv8D3. In vitro binding of 125I-labeled affibodies with and without scFv8D3 was evaluated by ELISA and autoradiography. Brain uptake and retention of the affibodies at 2 h and 24 h post injection was studied ex vivo in WT and transgenic (tg-Swe and tg-ArcSwe) mice. At 2 h post injection, [125I]I-Z5 and [125I]I-Z1 displayed brain concentrations of 0.37 ± 0.09% and 0.46 ± 0.08% ID/g brain, respectively. [125I]I-scFv8D3-Z5 and [125I]I-scFv8D3-Z1 showed increased brain concentrations of 0.53 ± 0.16% and 1.20 ± 0.35%ID/g brain. At 24 h post injection, brain retention of [125I]I-Z1 and [125I]I-Z5 was low, while [125I]I-scFv8D3-Z1 and [125I]I-scFv8D3-Z5 showed moderate brain retention, with a tendency towards higher retention of [125I]I-scFv8D3-Z5 in AD transgenic mice. Nuclear track emulsion autoradiography showed greater parenchymal distribution of [125I]I-scFv8D3-Z5 and [125I]I-scFv8D3-Z1 compared with the affibodies without scFv8D3, but could not confirm specific affibody accumulation around Aβ deposits. Affibody-scFv8D3 fusions displayed increased brain and parenchymal delivery compared with the non-fused affibodies. However, fast brain washout and a suboptimal balance between Aβ and mTfR1 affinity resulted in low intrabrain retention around Aβ deposits.
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| 5. |
- Govender, Rydvikha, 1989, et al.
(författare)
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High Content Solid Dispersions for Dose Window Extension: A Basis for Design Flexibility in Fused Deposition Modelling
- 2020
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Ingår i: Pharmaceutical Research. - : Springer Science and Business Media LLC. - 1573-904X .- 0724-8741. ; 37:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study uses high drug content solid dispersions for dose window extension beyond current demonstrations using fused deposition modelling (FDM) to; i) accommodate pharmaceutically relevant doses of drugs of varying potencies at acceptable dosage form sizes and ii) enable enhanced dose flexibility via modular dosage form design concepts. Methods: FDM was used to generate ~0.5 mm thick discs of varying diameter (2–10 mm) from melt-extruded feedstocks based on 10% to 50% w/w felodipine in ethyl cellulose. Drug content was determined by UV spectroscopy and dispensing precision from printed disc mass. Results: Mean felodipine content was within ±5% of target values for all print volumes and compositions including contents as high as ~50% w/w. However, poor dispensing precision was evident at all print volumes. Conclusions: In pursuit of dose flexibility, this successful demonstration of dose window extension using high content solid dispersions preserves FDM design flexibility by maintaining applicability to drugs of varying potencies. The achieved uniformity of content supports the application of varying content solid dispersions to modular dosage form concepts to enhance dose flexibility. However, poor dispensing precision impedes its utilisation until appropriate compatibility between FDM hardware and materials at varying drug contents can be attained.
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| 6. |
- Hedge, Oliver, 1991-, et al.
(författare)
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Suitability of Artificial Membranes in Lipolysis-Permeation Assays of Oral Lipid-Based Formulations
- 2020
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 37:6
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Tidskriftsartikel (refereegranskat)abstract
- PurposeTo evaluate the performance of artificial membranes in in vitro lipolysis-permeation assays useful for absorption studies of drugs loaded in lipid-based formulations (LBFs).MethodsPolycarbonate as well as PVDF filters were treated with hexadecane, or lecithin in n-dodecane solution (LiDo) to form artificial membranes. They were thereafter used as absorption membranes separating two compartments mimicking the luminal and serosal side of the intestine in vitro. Membranes were subjected to dispersions of an LBF that had been digested by porcine pancreatin and spiked with the membrane integrity marker Lucifer Yellow (LY). Three fenofibrate-loaded LBFs were used to explore the in vivo relevance of the assay.ResultsOf the explored artificial membranes, only LiDo applied to PVDF was compatible with lipolysis by porcine pancreatin. Formulation ranking based on mass transfer in the LiDo model exposed was the same as drug release in single-compartment lipolysis. Ranking based on observed apparent permeability coefficients of fenofibrate with different LBFs were the same as those obtained in a cell-based model.ConclusionsThe LiDo membrane was able to withstand lipolysis for a sufficient assay period. However, the assay with porcine pancreatin as digestive agent did not predict the in vivo ranking of the assayed formulations better than existing methods. Comparison with a Caco-2 based assay method nonetheless indicates that the in vitro in vivo relationship of this cell-free model could be improved with alternative digestive agents.
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| 7. |
- Leohr, Jennifer, et al.
(författare)
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Sweet/Fat Preference Taste in Subjects who are Lean, Obese and Very Obese
- 2020
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 37:12
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study assessed the perception of sweetness, creaminess, and pleasantness from a sweet/fat preference test in subjects who are lean (BMI: 19-25), obese (BMI: 30-33) or very obese (BMI: 34-40) using categorical modeling. Methods: Subjects tasted 16 dairy solutions consisting of 0%, 3.5%, 11.3% and 37.5% fat and each containing 0%, 5%, 10%, or 20% sugar and rated them for sweetness, creaminess and pleasantness.Results: A proportional odds model described the perception of sweetness using an Emax for the effect of sugar and a linear effect for fat. Perception of creaminess was dependent on the fat and sugar content and was described with proportional odd model with linear effects of sugar and fat. Perception of pleasantness increased with sugar and fat but decreased in solutions containing 37.5% fat. A differential odds model using an Emax model for fat and sugar with a negative interaction between them allowed the sugar content to be less than proportional and the fat content to be greater than proportional for pleasantness.Conclusion: Application of modeling provided understanding of these complex interactions of sugar and fat on the perception of sweetness, creaminess, and pleasantness and provides a tool to investigate obesity and pharmacological intervention.
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| 8. |
- Llanos-Paez, Carolina C., et al.
(författare)
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Improved Confidence in a Confirmatory Stage by Application of Item-Based Pharmacometrics Model : Illustration with a Phase III Active Comparator-Controlled Trial in COPD Patients
- 2022
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Ingår i: Pharmaceutical research. - : Springer Nature. - 0724-8741 .- 1573-904X. ; 39:8, s. 1779-1787
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The current study aimed to illustrate how a non-linear mixed effect (NLME) model-based analysis may improve confidence in a Phase III trial through more precise estimates of the drug effect. Methods The FULFIL clinical trial was a Phase III study that compared 24 weeks of once daily inhaled triple therapy with twice daily inhaled dual therapy in patients with chronic obstructive pulmonary disease (COPD). Patient reported outcome data, obtained by using The Evaluating Respiratory Symptoms in COPD (E-RS:COPD) questionnaire, from the FULFIL study were analyzed using an NLME item-based response theory model (IRT). The change from baseline (CFB) in E-RS:COPD total score over 4-week intervals for each treatment arm was obtained using the IRT and compared with published results obtained with a mixed model repeated measures (MMRM) analysis. Results The IRT included a graded response model characterizing item parameters and a Weibull function combined with an offset function to describe the COPD symptoms-time course in patients receiving either triple therapy (n = 907) or dual therapy (n = 894). The IRT improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of at least 3.64 times larger for the MMRM analysis to achieve the IRT precision in the CFB estimate. Conclusion This study shows the advantage of IRT over MMRM with a direct comparison of the same primary endpoint for the two analyses using the same observed clinical trial data, resulting in an increased confidence in Phase III.
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| 10. |
- Loryan, Irena, Associate Professor (Docent), 1977-, et al.
(författare)
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Unbound Brain-to-Plasma Partition Coefficient, K-p,K-uu,K-brain-a Game Changing Parameter for CNS Drug Discovery and Development
- 2022
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Ingår i: Pharmaceutical research. - : Springer Nature. - 0724-8741 .- 1573-904X. ; 39:7, s. 1321-1341
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Tidskriftsartikel (refereegranskat)abstract
- Purpose More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (K-p,K-uu,K-brain) by Prof. Margareta Hammarlund-Udenaes, which was enabled by advancements in experimental methodologies including cerebral microdialysis. Since then, growing knowledge and data continue to support the notion that the unbound (free) concentration of a drug at the site of action, such as the brain, is the driving force for pharmacological responses. Towards this end, K-p,K-uu,K-brain is the key parameter to obtain unbound brain concentrations from unbound plasma concentrations. Methods To understand the importance and impact of the K-p,K-uu,K-brain concept in contemporary drug discovery and development, a survey has been conducted amongst major pharmaceutical companies based in Europe and the USA. Here, we present the results from this survey which consisted of 47 questions addressing: 1) Background information of the companies, 2) Implementation, 3) Application areas, 4) Methodology, 5) Impact and 6) Future perspectives. Results and conclusions From the responses, it is clear that the majority of the companies (93%) has established a common understanding across disciplines of the concept and utility of K-p,K-uu,K-brain as compared to other parameters related to brain exposure. Adoption of the K-p,K-uu,K-brain concept has been mainly driven by individual scientists advocating its application in the various companies rather than by a top-down approach. Remarkably, 79% of all responders describe the portfolio impact of K-p,K-uu,K-brain implementation in their companies as 'game-changing'. Although most companies (74%) consider the current toolbox for K-p,K-uu,K-brain assessment and its validation satisfactory for drug discovery and early development, areas of improvement and future research to better understand human brain pharmacokinetics/pharmacodynamics translation have been identified.
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