| 1. |
- Lennernäs, Hans, et al.
(författare)
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Oral biopharmaceutics tools - Time for a new initiative - An introduction to the IMI project OrBiTo
- 2014
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 57:SI, s. 292-299
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Forskningsöversikt (refereegranskat)abstract
- OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silica biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.
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| 2. |
- Darwich, A. S., et al.
(författare)
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Interplay of Metabolism and Transport in Determining Oral Drug Absorption and Gut Wall Metabolism : A Simulation Assessment Using the "Advanced Dissolution, Absorption, Metabolism (ADAM)" Model
- 2010
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Ingår i: Current drug metabolism. - : Bentham Science Publishers Ltd.. - 1389-2002 .- 1875-5453. ; 11:9, s. 716-729
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Forskningsöversikt (refereegranskat)abstract
- Bioavailability of orally administered drugs can be influenced by a number of factors including release from the formulation, dissolution, stability in the gastrointestinal (GI) environment, permeability through the gut wall and first-pass gut wall and hepatic metabolism. Although there are various enzymes in the gut wall which may contribute to gut first pass metabolism, Cytochrome P450 (CYP) 3A has been shown to play a major role. The efflux transporter P-glycoprotein (P-gp; MDR1/ABCB1) is the most extensively studied drug efflux transporter in the gut and might have a significant role in the regulation of GI absorption. Although not every CYP3A substrate will have a high extent of gut wall first-pass extraction, being a substrate for the enzyme increases the likelihood of a higher first-pass extraction. Similarly, being a P-gp substrate does not necessarily pose a problem with the gut wall absorption however it may reduce bioavailability in some cases (e. g. when drug has low passive permeability). An on-going debate has focused on the issue of the interplay between CYP3A and P-gp such that high affinity to P-gp increases the exposure of drug to CYP3A through repeated cycling via passive diffusion and active efflux, decreasing the fraction of drug that escapes first pass gut metabolism (F-G). The presence of P-gp in the gut wall and the high affinity of some CYP3A substrates to this transporter are postulated to reduce the potential for saturating the enzymes, thus increasing gut wall first-pass metabolism for compounds which otherwise would have saturated CYP3A. Such inferences are based on assumptions in the modelling of oral drug absorption. These models should be as mechanistic as possible and tractable using available in vitro and in vivo information. We review, through simulation, this subject and examine the interplay between gut wall metabolism and efflux transporters by studying the fraction of dose absorbed into enterocytes (F-a) and F-G via systematic variation of drug characteristics, in accordance with the Biopharmaceutics Classification System (BCS) within one of the most physiological models of oral drug absorption currently available, respectively ADAM. Variables studied included the intrinsic clearance (CLint) and the Michaelis-Menten Constant (K-m) for CYP3A4 and P-gp (CLint-CYP3A4 and Km-CYP3A4, CLint-P-gp and Km-P-gp). The impact of CYP3A4 and P-gp intracellular topography were not investigated since a well-stirred enterocyte is assumed within ADAM. An increased CLint-CYP3A4 resulted in a reduced F-G whereas an increase in CLint-P-gp resulted in a reduced F-a, but interestingly decreased F-G too. The reduction in F-G was limited to certain conditions and was modest. Non-linear relationships between various parameters determining the permeability (e. g. P-app, CLint-P-gp, and Km-P-gp) and gut wall metabolism (e. g. CLint-CYP3A4, Km-CYP3A4) resulted in disproportionate changes in F-G compared to the magnitude of singular effects. The results suggest that P-gp efflux decreases enterocytic drug concentration for drugs given at reasonably high dose which possess adequate passive apparent permeability (high P-app), by de-saturating CYP3A4 in the gut resulting in a lower F-G. However, these findings were observed only in a very limited area of the parameters space matching very few herapeutic drugs (a group with very high metabolism, high turn-over by efflux transporters and low F-a). The systematic approach in this study enabled us to recognise the combination of parameter values where the potential interplay between metabolising enzymes and efflux transporters is expected to be highest, using a realistic range of parameter values taken from an intensive literature search.
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| 3. |
- Rostami, Elham, 1979-, et al.
(författare)
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BDNF polymorphism predicts general intelligence after penetrating traumatic brain injury
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:11, s. e27389-
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal plasticity is a fundamental factor in cognitive outcome following traumatic brain injury. Brain-derivedneurotrophic factor (BDNF), a member of the neurotrophin family, plays an important role in this process. While thereare many ways to measure cognitive outcome, general cognitive intelligence is a strong predictor of everyday decisionmaking,occupational attainment, social mobility and job performance. Thus it is an excellent measure of cognitive outcomefollowing traumatic brain injury (TBI). Although the importance of the single-nucleotide polymorphisms polymorphism oncognitive function has been previously addressed, its role in recovery of general intelligence following TBI is unknown. Wegenotyped male Caucasian Vietnam combat veterans with focal penetrating TBI (pTBI) (n = 109) and non-head injuredcontrols (n = 38) for 7 BDNF single-nucleotide polymorphisms. Subjects were administrated the Armed Forces QualificationTest (AFQT) at three different time periods: pre-injury on induction into the military, Phase II (10–15 years post-injury, andPhase III (30–35 years post-injury). Two single-nucleotide polymorphisms, rs7124442 and rs1519480, were significantlyassociated with post-injury recovery of general cognitive intelligence with the most pronounced effect at the Phase II timepoint, indicating lesion-induced plasticity. The genotypes accounted for 5% of the variance of the AFQT scores,independently of other significant predictors such as pre-injury intelligence and percentage of brain volume loss. Thesedata indicate that genetic variations in BDNF play a significant role in lesion-induced recovery following pTBI. Identifying theunderlying mechanism of this brain-derived neurotrophic factor effect could provide insight into an important aspect ofpost-traumatic cognitive recovery.
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| 4. |
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| 5. |
- Rostami, Elham, et al.
(författare)
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Proteomic-based identification of injury-specific patterns of biomarkers in rotational and penetrating TBI
- 2010
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Ingår i: 40th Neuroscience Conference, November 13-17, 2010, San Diego, USA. ; , s. Program 467.14, Poster AA14-
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Traumatic Brain Injury (TBI) biomarkers would be highly valuable in the diagnosis of various forms of TBI and also in evaluation and treatment of TBI patients and may even provide prediction of outcome of the future impairments of the patients. Here we use proteomics to investigate the temporal changes of chosen proteins in serum and brain in 2 different animal TBI models. Methods: The first model is a controlled penetration of 2 mm thick needle shaped object, which is accelerated with a bullet from air gun or a pendulum, pen-TBI. In the second model where we produce diffuse axonal injury, the animal is subjected to high-speed sagittal rotation acceleration, rot-TBI. The rats were sacrificed 1 day, 3 days and 14 days post injury. We used 30rats, 15rats in each model, 5 rats for each timepoint where 2 of these where sham, these results were compared with values from normal rats. The FC (FC) and HC (HC) were extracted in addition to serum samples. The tissue extractions were analyzed with reverse capture antibody based proteomics for N-cadherin, S-100B, Tau, NSE, NF200, TNF-a, MBP, BDNF, C3, C9, C5b9,Results: In brain significant changes could be seen in N-cadherin in HC in pen-TBI on day 1, BDNF showed a peak in rot-TBI on day 1 while in pen-TBI the peak was after 14 days. C3 increased significantly in the HC of rot-TBI at day 1. C9 increased significantly in rot-TBI both in FC and HC on day 3 and day1 and 3 respectively. C5b9 had its peak in HC in rot-TBI on day 1 but in pen-TBI at day14. N-cadherin in serum of rot-TBI showed a significant increase in day 1 and 14 with a nadir at day3. The pattern was different in pen-TBI where there was an increase at all timepoint with increase overtime. Tau in serum was significantly increased uniformly at all time points in both models. TNF-a was also increased at all timepoints but in rot-TBI it decreased by day 14. S-100B showed no significant change in rot-TBI while in pen-TBI it was significantly increased at all timepoints. NSE in rot-TBI had a peak at day 1 and declined but in pen-TBI there was a nadir at day 3 and the peak was reached by day14. Similar pattern was seen in NF200. MBP was increased at all timepoints with a peak at day 3 in both models. C3 was increased at all timepoints but in pen-TBI it had a peak in day 3. C9 in rot-TBI increased significantly at day 3 and 14 while in pen-TBI it increased from day1 till day 14. C5b9 was significantly increased at all timepoints in both models however in rot-TBI it increased overtime while in pen-TBI it had a peak on day 14.Conclusion: To the best of our knowledge these are the first results showing TBI – type specific changes in different proteins that can be considered as future biomarkers.
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| 6. |
- Vicini, P, et al.
(författare)
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Pharmacometrics and Systems Pharmacology Software Tutorials and Use : Comments and Guidelines for PSP Contributions
- 2013
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Ingår i: CPT. - : Wiley. - 2163-8306. ; 2, s. e86-
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Tidskriftsartikel (refereegranskat)abstract
- In addition to methodological Tutorials,(1) CPT:PSP has recently started to publish software Tutorials.(2,3) Our readership and authors may be wondering what kind of format or product is expected, and the review of submissions we have already received prompted several discussions within the PSP Editorial Team. This editorial reflects on these discussions and summarizes their salient points. It aims at providing some details about the current vision of CPT:PSP for software tutorial articles. In addition, it brings some clarity on the topic of what role commercial software tutorials can have in CPT:PSP and how CPT:PSP tutorials differ from publications which describe the software itself, as those which can be found in other computer science journals. Finally, the discussion includes reproducibility considerations and the general use of commercial and noncommercial software in CPT:PSP publications. We hope our thoughts, and especially a stated requirement to publish user input to the software to aid in reproducibility, will help in guiding our authors and will stimulate healthy debate among our readers about the evolving nature of our science, how it can be facilitated using software and associated databases as a conduit, and what role this journal can play in fostering both the best modeling and simulation practices and the best scientific approaches to computational modeling, to bring the advantages of modeling and simulation to all regular practitioners, and not to just a (self) selected few.
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