| 1. |
- Gatchell, Michael, et al.
(författare)
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Commissioning of the DESIREE storage rings - a new facility for cold ion-ion collisions
- 2014
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Ingår i: XXVIII International Conference on Photonic, Electronic and Atomic Collisions (ICPEAC 2013). - : Institute of Physics (IOP). ; 488:1
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Konferensbidrag (refereegranskat)abstract
- We report on the ongoing commissioning of the Double ElectroStatic Ion Ring ExpEriment, DESIREE, at Stockholm University. Beams of atomic carbon anions (C-) and smaller carbon anion molecules (C-2(-), C-3(-), C-4(-) etc.) have been produced in a sputter ion source, accelerated to 10 keV or 20 keV, and stored successfully in the two electrostatic rings. The rings are enclosed in a common vacuum chamber cooled to below 13 Kelvin. The DESIREE facility allows for studies of internally relaxed single isolated atomic, molecular and cluster ions and for collision experiments between cat-and anions down to very low center-of-mass collision energies (meV scale). The total thermal load of the vacuum chamber at this temperature is measured to be 32 W. The decay rates of stored ion beams have two components: a non-exponential component caused by the space charge of the beam itself which dominates at early times and an exponential term from the neutralization of the beam in collisions with residual gas at later times. The residual gas limited storage lifetime of carbon anions in the symmetric ring is over seven minutes while the 1/e lifetime in the asymmetric ring is measured to be about 30 seconds. Although we aim to improve the storage in the second ring, the number of stored ions are now sufficient for many merged beams experiments with positive and negative ions requiring milliseconds to seconds ion storage.
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| 2. |
- Gatchell, Michael, et al.
(författare)
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First results from the Double ElectroStatic Ion-Ring ExpEriment, DESIREE
- 2014
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Ingår i: XXVIII International Conference on Photonic, Electronic and Atomic Collisions (ICPEAC 2013). - : Institute of Physics (IOP). ; 488
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Konferensbidrag (refereegranskat)abstract
- We have stored the first beams in one of the rings of the double electrostatic ion-storage ring, DESIREE at cryogenic and at room temperature conditions. At cryogenic operations the following parameters are found. Temperature; T= 13K, pressure; p <10(-13) mbar, initial number of stored ions; N > 10(7) and storage lifetime of a C-2(-) beam; tau = 450 S.
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| 3. |
- Hartman, Henrik, et al.
(författare)
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First storage of ion beams in the Double Electrostatic Ion-Ring Experiment : DESIREE
- 2013
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Ingår i: Review of Scientific Instruments. - : American Institute of Physics (AIP). - 0034-6748 .- 1089-7623. ; 84:5
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Tidskriftsartikel (refereegranskat)abstract
- We report on the first storage of ion beams in the Double ElectroStatic Ion Ring ExpEriment, DESIREE, at Stockholm University. We have produced beams of atomic carbon anions and small carbon anion molecules (Cn-, n = 1, 2, 3, 4) in a sputter ion source. The ion beams were accelerated to 10 keV kinetic energy and stored in an electrostatic ion storage ring enclosed in a vacuum chamber at 13 K. For 10 keV C2- molecular anions we measure the residual-gas limited beam storage lifetime to be 448 s +/- 18 s with two independent detector systems. Using the measured storage lifetimes we estimate that the residual gas pressure is in the 10-14 mbar range. When high current ion beams are injected, the number of stored particles does not follow a single exponential decay law as would be expected for stored particles lost solely due to electron detachment in collision with the residual-gas. Instead, we observe a faster initial decay rate, which we ascribe to the effect of the space charge of the ion beam on the storage capacity.
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| 4. |
- Thomas, Richard D., et al.
(författare)
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DESIREE : Physics with cold stored ion beams
- 2015
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Ingår i: DR2013. - : EDP Sciences. ; 84, s. 01004-01004
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Konferensbidrag (refereegranskat)abstract
- Here we will briefly describe the commissioning of the Double ElectroStatic Ion Ring ExpEriment (DESIREE) facility at Stockholm University, Sweden. This device uses purely electrostatic focussing and deflection elements and allows ion beams of opposite charge to be confined under extreme high vacuum and cryogenic conditions in separate rings and then merged over a common straight section. This apparatus allows for studies of interactions between cations and anions at very low and well-defined centre-of-mass energies (down to a few meV) and at very low internal temperatures (down to a few K).
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| 5. |
- Thomas, Richard D., et al.
(författare)
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The double electrostatic ion ring experiment : A unique cryogenic electrostatic storage ring for merged ion-beams studies
- 2011
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Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 82:6, s. 065112-
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Tidskriftsartikel (refereegranskat)abstract
- We describe the design of a novel type of storage device currently under construction at Stockholm University, Sweden, using purely electrostatic focussing and deflection elements, in which ion beams of opposite charges are confined under extreme high vacuum cryogenic conditions in separate rings and merged over a common straight section. The construction of this double electrostatic ion ring experiment uniquely allows for studies of interactions between cations and anions at low and well-defined internal temperatures and centre-of-mass collision energies down to about 10 K and 10 meV, respectively. Position sensitive multi-hit detector systems have been extensively tested and proven to work in cryogenic environments and these will be used to measure correlations between reaction products in, for example, electron-transfer processes. The technical advantages of using purely electrostatic ion storage devices over magnetic ones are many, but the most relevant are: electrostatic elements which are more compact and easier to construct; remanent fields, hysteresis, and eddy-currents, which are of concern in magnetic devices, are no longer relevant; and electrical fields required to control the orbit of the ions are not only much easier to create and control than the corresponding magnetic fields, they also set no upper mass limit on the ions that can be stored. These technical differences are a boon to new areas of fundamental experimental research, not only in atomic and molecular physics but also in the boundaries of these fields with chemistry and biology. For examples, studies of interactions with internally cold molecular ions will be particular useful for applications in astrophysics, while studies of solvated ionic clusters will be of relevance to aeronomy and biology.
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| 6. |
- Fagerholm, Urban, et al.
(författare)
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Advances in Predictions of Oral Bioavailability of Candidate Drugs in Man with New Machine Learning Methodology
- 2021
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Ingår i: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 26:9
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Tidskriftsartikel (refereegranskat)abstract
- Oral bioavailability (F) is an essential determinant for the systemic exposure and dosing regimens of drug candidates. F is determined by numerous processes, and computational predictions of human estimates have so far shown limited results. We describe a new methodology where F in humans is predicted directly from chemical structure using an integrated strategy combining 9 machine learning models, 3 sets of structural alerts, and 2 physiologically-based pharmacokinetic models. We evaluate the model on a benchmark dataset consisting of 184 compounds, obtaining a predictive accuracy (Q2) of 0.50, which is successful according to a pharmaceutical industry proposal. Twenty-seven compounds were found (beforehand) to be outside the main applicability domain for the model. We compare our results with interspecies correlations (rat, mouse and dog vs. human) using the same dataset, where animal vs. human-correlations (R2) were found to be 0.21 to 0.40 and maximum prediction errors were smaller than maximum interspecies differences. We conclude that our method has sufficient predictive accuracy to be practically useful with applications in human exposure and dose predictions, compound optimization and decision making, with potential to rationalize drug discovery and development and decrease failures and overexposures in early clinical trials with candidate drugs.
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| 7. |
- Fagerholm, Urban, et al.
(författare)
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Comparison between lab variability and in silico prediction errors for the unbound fraction of drugs in human plasma
- 2021
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Ingår i: Xenobiotica. - : Taylor & Francis. - 0049-8254 .- 1366-5928. ; 51:10, s. 1095-1100
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Tidskriftsartikel (refereegranskat)abstract
- Variability of the unbound fraction in plasma (f(u)) between labs, methods and conditions is known to exist. Variability and uncertainty of this parameter influence predictions of the overall pharmacokinetics of drug candidates and might jeopardise safety in early clinical trials. Objectives of this study were to evaluate the variability of human in vitro f(u)-estimates between labs for a range of different drugs, and to develop and validate an in silico f(u)-prediction method and compare the results to the lab variability. A new in silico method with prediction accuracy (Q(2)) of 0.69 for log f(u) was developed. The median and maximum prediction errors were 1.9- and 92-fold, respectively. Corresponding estimates for lab variability (ratio between max and min f(u) for each compound) were 2.0- and 185-fold, respectively. Greater than 10-fold lab variability was found for 14 of 117 selected compounds. Comparisons demonstrate that in silico predictions were about as reliable as lab estimates when these have been generated during different conditions. Results propose that the new validated in silico prediction method is valuable not only for predictions at the drug design stage, but also for reducing uncertainties of f(u)-estimations and improving safety of drug candidates entering the clinical phase.
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| 8. |
- Fagerholm, Urban, et al.
(författare)
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In Silico Prediction of Human Clinical Pharmacokinetics with ANDROMEDA by Prosilico : Predictions for an Established Benchmarking Data Set, a Modern Small Drug Data Set, and a Comparison with Laboratory Methods
- 2023
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Ingår i: ATLA (Alternatives to Laboratory Animals). - : SAGE Publications. - 0261-1929. ; 51:1, s. 39-54
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Tidskriftsartikel (refereegranskat)abstract
- There is an ongoing aim to replace animal and in vitro laboratory models with in silico methods. Such replacement requires the successful validation and comparably good performance of the alternative methods. We have developed an in silico prediction system for human clinical pharmacokinetics, based on machine learning, conformal prediction and a new physiologically-based pharmacokinetic model, i.e. ANDROMEDA. The objectives of this study were: a) to evaluate how well ANDROMEDA predicts the human clinical pharmacokinetics of a previously proposed benchmarking data set comprising 24 physicochemically diverse drugs and 28 small drug molecules new to the market in 2021; b) to compare its predictive performance with that of laboratory methods; and c) to investigate and describe the pharmacokinetic characteristics of the modern drugs. Median and maximum prediction errors for the selected major parameters were ca 1.2 to 2.5-fold and 16-fold for both data sets, respectively. Prediction accuracy was on par with, or better than, the best laboratory-based prediction methods (superior performance for a vast majority of the comparisons), and the prediction range was considerably broader. The modern drugs have higher average molecular weight than those in the benchmarking set from 15 years earlier (ca 200 g/mol higher), and were predicted to (generally) have relatively complex pharmacokinetics, including permeability and dissolution limitations and significant renal, biliary and/or gut-wall elimination. In conclusion, the results were overall better than those obtained with laboratory methods, and thus serve to further validate the ANDROMEDA in silico system for the prediction of human clinical pharmacokinetics of modern and physicochemically diverse drugs.
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| 9. |
- Fagerholm, Urban, et al.
(författare)
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In silico prediction of volume of distribution of drugs in man using conformal prediction performs on par with animal data-based models
- 2021
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Ingår i: Xenobiotica. - : Taylor & Francis. - 0049-8254 .- 1366-5928. ; 51:12, s. 1366-1371
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Tidskriftsartikel (refereegranskat)abstract
- Volume of distribution at steady state (Vss) is an important pharmacokinetic endpoint. In this study we apply machine learning and conformal prediction for human Vss prediction, and make a head-to-head comparison with rat-to-man scaling, allometric scaling and the Rodgers-Lukova method on combined in silico and in vitro data, using a test set of 105 compounds with experimentally observed Vss.The mean prediction error and % with <2-fold prediction error for our method were 2.4-fold and 64%, respectively. 69% of test compounds had an observed Vss within the prediction interval at a 70% confidence level. In comparison, 2.2-, 2.9- and 3.1-fold mean errors and 69, 64 and 61% of predictions with <2-fold error was reached with rat-to-man and allometric scaling and Rodgers-Lukova method, respectively.We conclude that our method has theoretically proven validity that was empirically confirmed, and showing predictive accuracy on par with animal models and superior to an alternative widely used in silico-based method. The option for the user to select the level of confidence in predictions offers better guidance on how to optimise Vss in drug discovery applications.
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| 10. |
- Fagerholm, Urban, et al.
(författare)
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In Silico Predictions of the Gastrointestinal Uptake of Macrocycles in Man Using Conformal Prediction Methodology
- 2022
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier. - 0022-3549 .- 1520-6017. ; 111:9, s. 2614-2619
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Tidskriftsartikel (refereegranskat)abstract
- The gastrointestinal uptake of macrocyclic compounds is not fully understood. Here we applied our previously validated integrated system based on machine learning and conformal prediction to predict the passive fraction absorbed (f(a)), maximum fraction dissolved (f(diss)), substrate specificities for major efflux transporters and total fraction absorbed (f(a,tot)) for a selected set of designed macrocyclic compounds (n = 37; MW 407-889 g/mol) and macrocyclic drugs (n = 16; MW 734-1203 g/mole) in vivo in man. Major aims were to increase the understanding of oral absorption of macrocycles and further validate our methodology. We predicted designed macrocycles to have high f(a )and low to high f(diss) and f(a,tot, )and average estimates were higher than for the larger macrocyclic drugs. With few exceptions, compounds were predicted to be effluxed and well absorbed. A 2-fold median prediction error for f(a,tot )was achieved for macrocycles (validation set). Advantages with our methodology include that it enables predictions for macrocycles with low permeability, Caco-2 recovery and solubility (BCS IV), and provides prediction intervals and guides optimization of absorption. The understanding of oral absorption of macrocycles was increased and the methodology was validated for prediction of the uptake of macrocycles in man.(C) 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.
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