| 1. |
- Chen, Chunli, et al.
(författare)
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Assessing Pharmacodynamic Interactions in Mice using the Multistate Tuberculosis Pharmacometric and General Pharmacodynamic Interaction Models
- 2017
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Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 6:11, s. 787-797
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this study was to investigate pharmacodynamic (PD) interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics (PKs), the Multistate Tuberculosis Pharmacometric (MTP) model, and the General Pharmacodynamic Interaction (GPDI) model. Rifampicin, isoniazid, ethambutol, or pyrazinamide were administered in monotherapy for 4 weeks. Rifampicin and isoniazid showed effects in monotherapy, whereas the animals became moribund after 7 days with ethambutol or pyrazinamide alone. No PD interactions were observed against fast-multiplying bacteria. Interactions between rifampicin and isoniazid on killing slow and non-multiplying bacteria were identified, which led to an increase of 0.86 log(10) colony-forming unit (CFU)/lungs at 28 days after treatment compared to expected additivity (i.e., antagonism). An interaction between rifampicin and ethambutol on killing non-multiplying bacteria was quantified, which led to a decrease of 2.84 log(10) CFU/lungs at 28 days after treatment (i.e., synergism). These results show the value of pharmacometrics to quantitatively assess PD interactions in preclinical tuberculosis drug development.
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| 2. |
- Chen, Chunli, et al.
(författare)
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Comparisons of analysis methods for assessment of pharmacodynamic interactions including design recommendations
- 2018
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Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative evaluation of potential pharmacodynamic (PD) interactions is important in tuberculosis drug development in order to optimize Phase 2b drug selection and ultimately to define clinical combination regimens. In this work, we used simulations to (1) evaluate different analysis methods for detecting PD interactions between two hypothetical anti-tubercular drugs in in vitro time-kill experiments, and (2) provide design recommendations for evaluation of PD interactions. The model used for all simulations was the Multistate Tuberculosis Pharmacometric (MTP) model linked to the General Pharmacodynamic Interaction (GPDI) model. Simulated data were re-estimated using the MTP–GPDI model implemented in Bliss Independence or Loewe Additivity, or using a conventional model such as an Empirical Bliss Independence-based model or the Greco model based on Loewe Additivity. The GPDI model correctly characterized different PD interactions (antagonism, synergism, or asymmetric interaction), regardless of the underlying additivity criterion. The commonly used conventional models were not able to characterize asymmetric PD interactions, i.e., concentration-dependent synergism and antagonism. An optimized experimental design was developed that correctly identified interactions in ≥ 94% of the evaluated scenarios using the MTP–GPDI model approach. The MTP–GPDI model approach was proved to provide advantages to other conventional models for assessing PD interactions of anti-tubercular drugs and provides key information for selection of drug combinations for Phase 2b evaluation.
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| 3. |
- Chen, Chunli
(författare)
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Pharmacokinetic-Pharmacodynamic Evaluations and Experimental Design Recommendations for Preclinical Studies of Anti-tuberculosis Drugs
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tuberculosis is an ancient infectious disease and a leading cause of death globally. Preclinical research is important for defining drugs and regimens which should be carried forward to human studies. This thesis aims to characterize the population pharmacokinetics and exposure-response relationships of anti-tubercular drugs alone and in combinations, and to suggest experimental designs for preclinical settings.The population pharmacokinetics of rifampicin, isoniazid, ethambutol and pyrazinamide were described for the first time in two mouse models. This allowed for linking the population pharmacokinetic model to the Multistate Tuberculosis Pharmacometric (MTP) model for biomarker response, which was used to characterize exposure-response relationships in monotherapy. Pharmacodynamic interactions in combination therapies were quantitatively described by linking the MTP model to the General Pharmacodynamic Interaction (GPDI) model, which provided estimates of single drug effects together with a quantitative model-based evaluation framework for evaluation of pharmacodynamic interactions among drugs in combinations. Synergism (more than expected additivity) was characterized between rifampicin and ethambutol, while antagonism (less than expected additivity) was characterized between rifampicin and isoniazid in combination therapies.The new single-dose pharmacokinetic design with enrichened individual sampling was more informative than the original design, in which only one sample was taken from each mouse in the pharmacokinetic studies. The new oral zipper design allows for informative pharmacokinetic sampling in a multiple-dose administration scenario for characterizing pharmacokinetic-pharmacodynamic relationships, with similar or lower bias and imprecision in parameter estimates and with a decreased total number of animals required by up to 7-fold compared to the original design. The optimized design for assessing pharmacodynamic interactions in the combination therapies, which was based on EC20, EC50 and EC80 of the single drug, provided lower bias and imprecision than a conventional reduced four-by-four microdilution checkerboard design at the same total number of samples required, which followed the 3Rs of animal welfare.In summary, in this thesis the population pharmacokinetic-pharmacodynamic models of first-line drugs in mice were characterized through linking each population pharmacokinetic model to the MTP model. Pharmacodynamic interactions were quantitatively illustrated by the MTP-GPDI model. Lastly, experimental designs were optimized and recommended to both pharmacokinetic and pharmacodynamic studies for preclinical settings.
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| 4. |
- Chen, Chunli, et al.
(författare)
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Population pharmacokinetics, optimised design and sample size determination for rifampicin, isoniazid, ethambutol and pyrazinamide in the mouse
- 2016
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 93, s. 319-333
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Tidskriftsartikel (refereegranskat)abstract
- The current first-line therapy for drug-susceptible tuberculosis consists of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). In this study, we determined the population pharmacokinetics (PopPK) of RIF, INH, EMB and PZA using original experimental sampling designs for single-dose intravenous (IV) and single- and multiple-dose oral administration studies in the mouse model, and used these PopPK models to develop and evaluate new, more informative sampling designs with the aim of reducing the number of animals required for each drug. The RIF, INH, EMB and PZA blood concentrations after single oral and IV doses and multiple-dose oral administrations based on the original designs were used in the PopPK analysis using NONMEM software. The final PopPK models described the data well, Stochastic simulation and estimation were used to optimise the designs. The relative bias and relative imprecision of each pharmacokinetic parameter for each drug were derived and assessed to choose the final designs. The final single-dose IV and oral designs included up to eight samples per mouse with a total of 24 mice required for RIF and EMB and 33 mice for INH and PZA. In the new multiple-dose (zipper) oral designs, the mice were divided into two groups of three per dose, and four samples were taken from each mouse to cover all seven or eight sampling time points. The final number of mice required for the multiple-dose oral designs was 30 for RIF, INH and EMB, 36 for PZA. The number of mice required in the new designs for RIF, INH and EMB was decreased by up to 7-fold and the relative bias and relative imprecision in the parameter estimates were at least similar to those in the original designs.
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| 5. |
- Chen, Chunli, et al.
(författare)
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The multistate tuberculosis pharmacometric model : a semi-mechanistic pharmacokinetic-pharmacodynamic model for studying drug effects in an acute tuberculosis mouse model
- 2017
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 44:2, s. 133-141
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Tidskriftsartikel (refereegranskat)abstract
- The Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin on Mycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected with M. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day). Twenty-five mice received oral rifampicin (1, 3, 9, 26 or 98 mg·kg-1·day-1; Days 1–8; 5 each dose level) and were sacrificed on Day 9. Twenty mice received oral rifampicin (30 mg·kg-1·day-1; up to 8 days) and were sacrificed on Days 2, 3, 4 and 9 (5 each day). The MTP model was linked to a rifampicin population pharmacokinetic model to describe the change in colony forming units (CFU) in the lungs over time. The transfer rates between the different bacterial states were fixed to estimates from in vitro data. The MTP model described well the change in CFU over time after different exposure levels of rifampicin in an acute tuberculosis mouse model. Rifampicin significantly inhibited the growth of fast-multiplying bacteria and stimulated the death of fast- and slow-multiplying bacteria. The data did not support an effect of rifampicin on non-multiplying bacteria possibly due to the short duration of the study. The pharmacometric modelling framework using the MTP model can be used to perform investigations and predictions of the efficacy of anti-tubercular drugs against different bacterial states.
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| 6. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 7. |
- Kang, Mingliang, et al.
(författare)
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Redox reaction of aqueous selenite with As-rich pyrite from Jiguanshanore mine (China) : reaction products and pathway
- 2014
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Ingår i: Applied Geochemistry. - : Elsevier BV. - 0883-2927 .- 1872-9134. ; 47, s. 130-140
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Tidskriftsartikel (refereegranskat)abstract
- The interaction of an As-rich natural pyrite (FeS2.08As0.043) with aqueous Se(IV) was investigated as a function of pH, ferrous iron concentration, and reaction time. Arsenic is often the most abundant minor constituent of natural pyrite, and is believed to substitute for S in the pyrite structure. EXAFS measurements confirmed the presence of AsS dianion group, with arsenic in the same local configuration as in the arsenopyrite. Speciation studies indicated that Se(0) was the unique reduction product in the pH range 5.05–8.65 over a reaction period of >1 month, while trace amounts of FeSeO3 might be formed at pH ⩟ 6.10. At pH > 6.07, the formation of Fe(III)-(oxyhydr)oxide is kinetically favored, and it consumed nearly all the aqueous iron, including the extra added Fe2+, thereby inhibiting the formation of the thermodynamically most stable product: FeSe2. After oxidation by Se(IV), the occurrence of surface S0, significant aqueous sulfur deficit, and excessive leaching of arsenic in solution, indicate the preferential release of As impurity via arsenopyrite oxidation. The data suggest that the polysulfide-elemental sulfur pathway, which prevails in acid-soluble metal sulfides, is an important pathway in the oxidation of As-rich pyrite, in addition to the thiosulfate pathway for acid-insoluble pyrite. Control experiments on As-free natural pyrite further support this mechanism. This study confirms the potential of reductive precipitation to attenuate the mobility of Se in the environment and demonstrates that minor elements commonly present in natural pyrite can play a significant role on its dissolution pathway.
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| 8. |
- Wang, Lanjing, et al.
(författare)
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Non-linear effects of the built environment and social environment on bus use among older adults in china : An application of the xgboost model
- 2021
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1661-7827 .- 1660-4601. ; 18:18
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Tidskriftsartikel (refereegranskat)abstract
- Global aging has raised increasing concerns on the health and well-being of older adults. Public transport is a viable option to improve the mobility and quality of life among older adults. However, policies that promote the public transport use among older adults are rare. This study utilizes the eXtreme Gradient Boosting (XGBoost) decision tree to explore the non-linear associations of the built and social environment with bus use among older adults in China. The bus use of older adults was obtained from the Zhongshan Household Travel Survey (ZHTS) in 2012. Results show that non-linear relationships exist among all built environment and social environment characteristics. Within certain thresholds, the percentage of green space land use, land use mixture, bus-stop density, and dwelling unit density are positively related to bus use among older adults. Like-wise, one social environment variable, the proportion of older adults in a neighborhood, is the key social environment variable. Furthermore, the dwelling unit density and proportion of older adults appear to have an inverse U-shaped relationship. Additionally, age, ownership of motorcycles, and distance from home to the nearest bus stop also show non-linearity. The findings presented in this paper facilitate effective planning interventions to promote bus use among older adults.
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| 9. |
- Wang, Wenxiao, et al.
(författare)
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Nonlinear associations of the built environment with cycling frequency among older adults in Zhongshan, China
- 2021
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1661-7827 .- 1660-4601. ; 18:20
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Tidskriftsartikel (refereegranskat)abstract
- The health and welfare of older adults have raised increasing attention due to global aging. Cycling is a physical activity and mode of transportation to enhance the mobility and quality of life among older adults. Nevertheless, the planning strategies to promote cycling among older adults are underutilized. Therefore, this paper describes the nonlinear associations of the built environment with cycling frequency among older adults. The data were collected from the Zhongshan Household Travel Survey (ZHTS) in 2012. The modeling approach was the eXtreme Gradient Boosting (XGBoost) model. The findings demonstrated that nonlinear relationships exist among all the selected built environment attributes. Within specific intervals, the population density, the land-use mixture, the distance from home to the nearest bus stop, and the distance from home to CBD are positively correlated to the cycling among older adults. Additionally, an inverse “U”-shaped relationship appears in the percentage of green space land use among all land uses. Moreover, the intersection density is inversely related to the cycling frequency among older adults. These findings provide nuanced and appropriate guidance for establishing age-friendly neighborhoods.
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| 10. |
- Wicha, Sebastian G., et al.
(författare)
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A general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Assessment of pharmacodynamic (PD) drug interactions is a cornerstone of the development of combination drug therapies. To guide this venture, we derive a general pharmacodynamic interaction (GPDI) model for ≥2 interacting drugs that is compatible with common additivity criteria. We propose a PD interaction to be quantifiable as multidirectional shifts in drug efficacy or potency and explicate the drugs’ role as victim, perpetrator or even both at the same time. We evaluate the GPDI model against conventional approaches in a data set of 200 combination experiments in Saccharomyces cerevisiae: 22% interact additively, a minority of the interactions (11%) are bidirectional antagonistic or synergistic, whereas the majority (67%) are monodirectional, i.e., asymmetric with distinct perpetrators and victims, which is not classifiable by conventional methods. The GPDI model excellently reflects the observed interaction data, and hence represents an attractive approach for quantitative assessment of novel combination therapies along the drug development process.
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| 11. |
- Xia, Tianwen, et al.
(författare)
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Comparison of GaN LED Optical Simulation in 2D and 3D Space Based on k-Domain Analysis Method
- 2024
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Ingår i: IEEE Journal of Quantum Electronics. - 0018-9197 .- 1558-1713. ; 60:3
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Tidskriftsartikel (refereegranskat)abstract
- Earlier researchers have designed nanostructures such as stripe gratings (SG) or photonic crystals array (PhCA) to improve the light extraction efficiency (LEE) of light-emitting diodes (LEDs) by the diffraction mechanism. However, through k-domain method and simulation analysis, this letter finds that although SG perform well in 2D simulation, their effect drops sharply in 3D space, a phenomenon being overlooked in the community. This letter explains the diffraction mechanism of LEDs with nanostructure in 2D and 3D space through K-domain analysis, and reveals the inaccuracy of simulating LED with SG in 2D space. Unlike SG, PhCA offers diffraction in two directions and may be more suitable for LEDs.
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