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Zeitschriftenartikel zum Thema "PopPK"
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Lavie, Muriel, Benjamin Seunes, Philippe Prior und Christian Boucher. „Distribution and Sequence Analysis of a Family of Type III-Dependent Effectors Correlate with the Phylogeny of Ralstonia solanacearum Strains“. Molecular Plant-Microbe Interactions® 17, Nr. 8 (August 2004): 931–40. http://dx.doi.org/10.1094/mpmi.2004.17.8.931.
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In Ralstonia solanacearum, we previously have reported on the characterization of popP1 and popP2 genes. These genes encode type III-dependent pathogenicity effectors related to the large family of AvrRxv/YopJ cysteine prote-ases that are shared among pathogens of plants and animals. In this study, we identify a third gene, named popP3, that is inactivated in the genome sequence of strain GMI1000 by insertion of a copy of the insertion sequence ISRso13. The three popP genes are localized on two large chromosomal pathogenicity islands, with popP1 and popP2 being present on the same island. Phylogenic analysis demonstrated that the PopP2 and PopP3 proteins are clearly distinct from other effectors of this family previously characterized in plant and animal pathogens. Analysis of the distribution and allelic variations of the three genes in 30 strains representative of the biodiversity of R. solanacearum established that popP genes are distributed widely among strains from two of the three phyla previously defined on the basis of the structure of the core genome. Sequencing of the popP genes from the different strains revealed limited allelic variations at the three loci but did not show evidence of recombination between the popP genes. Limited allelic variation together with occurrence of insertion sequences within or in the close vicinity of popP genes and the presence of gene duplications in these pathogenicity islands suggest that genomic rearrangements might be a major evolutionary driving force controlling evolution of the genes encoded in these regions. The implications of these observations in terms of bacterial evolution, gene acquisition, and horizontal gene transfers are discussed.
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Sepúlveda, Carlos, Oscar Montiel, José M. Cornejo Bravo und Roberto Sepúlveda. „Fuzzy Evaluation of Pharmacokinetic Models“. Computational Intelligence and Neuroscience 2018 (01.11.2018): 1–10. http://dx.doi.org/10.1155/2018/1983897.
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Population pharmacokinetic (PopPK) models allow researchers to predict and analyze drug behavior in a population of individuals and to quantify the different sources of variability among these individuals. In the development of PopPK models, the most frequently used method is the nonlinear mixed effect model (NLME). However, once the PopPK model has been developed, it is necessary to determine if the selected model is the best one of the developed models during the population pharmacokinetic study, and this sometimes becomes a multiple criteria decision making (MCDM) problem, and frequently, researchers use statistical evaluation criteria to choose the final PopPK model. The used evaluation criteria mentioned above entail big problems since the selection of the best model becomes susceptible to the human error mainly by misinterpretation of the results. To solve the previous problems, we introduce the development of a software robot that can automate the task of selecting the best PopPK model considering the knowledge of human expertise. The software robot is a fuzzy expert system that provides a method to systematically perform evaluations on a set of candidate PopPK models of commonly used statistical criteria. The presented results strengthen our hypothesis that the software robot can be successfully used to evaluate PopPK models ensuring the selection of the best PopPK model.
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Zuo, Fenghua, Jun Li und Xiaoyong Sun. „Exploring Population Pharmacokinetic Modeling with Resampling Visualization“. BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/585687.
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Background. In the last decade, population pharmacokinetic (PopPK) modeling has spread its influence in the whole process of drug research and development. While targeting the construction of the dose-concentration of a drug based on a population of patients, it shows great flexibility in dealing with sparse samplings and unbalanced designs. The resampling approach has been considered an important statistical tool to assist in PopPK model validation by measuring the uncertainty of parameter estimates and evaluating the influence of individuals.Methods. The current work describes a graphical diagnostic approach for PopPK models by visualizing resampling statistics, such as case deletion and bootstrap. To examine resampling statistics, we adapted visual methods from multivariate analysis, parallel coordinate plots, and multidimensional scaling.Results. Multiple models were fitted, the information of parameter estimates and diagnostics were extracted, and the results were visualized. With careful scaling, the dependencies between different statistics are revealed. Using typical examples, the approach proved to have great capacity to identify influential outliers from the statistical perspective, which deserves special attention in a dosing regimen.Discussion. By combining static graphics with interactive graphics, we are able to explore the multidimensional data from an integrated and systematic perspective. Complementary to current approaches, our proposed method provides a new way for PopPK modeling analysis.
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Borghorst, Stephan, Rob Pieters, Hans Juergen Kuehnel, Joachim Boos und Georg Hempel. „Population Pharmacokinetic of Native Escherichia Coli Asparaginase.“ Blood 114, Nr. 22 (20.11.2009): 4803. http://dx.doi.org/10.1182/blood.v114.22.4803.4803.
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Abstract Abstract 4803 Introduction Native Escherichia Coli Asparaginase (ASNase) is an integral component in the therapy of acute lymphoblastic leukemia (ALL) and non-Hodgkin's Lymphoma (NHL). There is a great interindividual variability in treatment intensity in patients treated with the same dose of ASNase. Population pharmacokinetics (PopPK) provides the possibility to divide the overall variability of a population in an inter- and intraindividual element and to develop more precise dosing recommendations. Furthermore, pharmacokinetic parameters can be estimated as well as possible covariates that may influence the pharmacokinetics of the drug can be identified. Patients and Methods The model building dataset consisted of 16 patients (233 samples) receiving 5000 U/m2 ASNase (Asparaginase Medac®) 8 times according to the DCOG-ALL 10 treatment protocol. Asparaginase activity was measured in a randomized clinical Phase 2 study comparing the pharmacokinetic and pharmacodynamic of a newly developed recombinant ASNase with that of the established ASNase (Asparaginase Medac®)[R. Pieters et al. Blood. 2008 Dec 15. 112(13):4832-8]. The PopPK-model was developed using NONMEM (version VI) with First Order Conditional Estimation (FOCE) method and INTERACTION option. Results A linear 2-compartmental model with a combined proportional (0.9%) and additive (48.1U/l) error model described the data adequately. The pharmacokinetic parameters estimated were: Total systemic clearance 0.135 ± 12.8% l/h/70kg, volume of distribution of the central compartment 4.27 ± 13.1% l/70kg, volume of distribution in the peripheral compartment 0.83 ± 80.4% l/70kg and intercompartmental clearance 0.058 l/h/70kg (mean ± interindividual variability). Body weight was identified as the most important covariate. Validity of the model was verified by simulating different dosages of ASNase (2500U/m2 and 10000U/m2) in induction and reinduction of the ALL-BFM treatment protocol. The median and mean ASNase activity was compared with published data [E. Ahlke et al. Br J Haematol. 1997 Mar. 96(4):675-81 and Boos et al. Eur J Cancer. 1996 Aug. 32A(9):1544-50]. Furthermore pharmacokinetic data obtained by a noncompartmental analysis [R. Pieters et al. Blood. 2008 Dec 15.112(13):4832-8] were compared with the pharmacokinetic data estimated by the PopPK model. Both procedures indicated on face validity of the PopPK model. Conclusion This PopPK analysis provides the first step in the development of a PopPK model for ASNase. Face validity of the PopPK model could be demonstrated and will be confirmed with an independent dataset. Disclosures: Pieters: Medac GmbH: Research Funding. Kuehnel:Medac GmbH: Employment. Boos:Medac GmbH: Honoraria. Hempel:Medac GmbH: Honoraria.
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Song, Ling, Cheng Cui, Ying Zhou, Zhongqi Dong, Zhiheng Yu, Yifan Xu, Tianyan Zhou et al. „Toward Greater Insights on Applications of Modeling and Simulation in Pregnancy“. Current Drug Metabolism 21, Nr. 9 (14.12.2020): 722–41. http://dx.doi.org/10.2174/1389200221666200907143941.
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Pregnant women are often excluded from routine clinical trials. Consequently, appropriate dosing regimens for majority of drugs are unknown in this population, which may lead to unexpected safety issue or insufficient efficacy in this un-studied population. Establishing evidence through the conduct of clinical studies in pregnancy is still a challenge. In recent decades, physiologically-based pharmacokinetic (PBPK) modeling has proven to be useful to support dose selection under various clinical scenarios, such as renal and/or liver impairment, drug-drug interactions, and extrapolation from adult to children. By integrating gestational-dependent physiological characteristics and drug-specific information, PBPK models can be used to predict PK during pregnancy. Population pharmacokinetic (PopPK) modeling approach also could complement pregnancy clinical studies by its ability to analyze sparse sampling data. In the past five years, PBPK and PopPK approaches for pregnancy have made significant progress. We reviewed recent progress, challenges and potential solutions for the application of PBPK, PopPK, and exposure-response analysis in clinical drug development for pregnancy.
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Li, Anning, Shuangmin Ji, Weihua Yue, Hao Yan, Fang Dong, Canjun Ruan, Wenbiao Li, Wei Lu, Dai Zhang und Chuanyue Wang. „Development of a population pharmacokinetic model of olanzapine for Chinese health volunteers and patients with schizophrenia“. BMJ Open 8, Nr. 8 (August 2018): e020070. http://dx.doi.org/10.1136/bmjopen-2017-020070.
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ObjectiveOlanzapine is an atypical antipsychotic drug commonly used for the treatment of schizophrenia. However, there are still many complications associated with the use of olanzapine, and researchers continually strive to improve the handling of data from regular therapeutic drug monitoring (TDM). The objective of this study is to optimise the individualised treatment of olanzapine by establishing a population pharmacokinetics (PopPK) model in Chinese patients with schizophrenia.MethodsThis study integrates an extensive collection of concentration data from healthy volunteers after a single dose and a less extensive collection of samples from patients undergoing TDM. A PopPK model was developed using non-linear mixed-effects modelling. Potential covariates, including the olanzapine manufacturer and patient gender and age, were assessed during model development. A total of 616 plasma concentration levels from 22 healthy male individuals in China and 458 concentration levels from 112 male and 122 female patients with schizophrenia undergoing TDM at 12 hospitals in China were included in the analysis. The concentration profile could be best described using a two-compartment model with first-order absorption and elimination.ResultsThe absorption rate (Ka) of olanzapine ranged from 2.85 h–1to 5.39 h–1for the different formulations. The typical absorption time delay was 0.877 hour. Body weight had a considerable effect on the apparent volume of the centre compartment and showed a power relationship.ConclusionsA PopPK model of olanzapine in Chinese patients with schizophrenia was developed in this study. After determining the PK parameters of olanzapine, the results suggested that body weight exhibited a considerable impact effect on VC/F. The impact of subjects and formulations requires further study. The PopPK model established in this study is likely to provide some information for the individualised therapy of olanzapine.Trial registration numberChiCTR-TRC-10000934; Results.
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Wang, Z., B. Verstockt, S. Vermeire, J. Sabino, M. Ferrante, P. Declerck und E. Dreesen. „P307 Modelling of the relationship between ustekinumab exposure, faecal calprotectin and endoscopic outcomes in patients with Crohn’s disease“. Journal of Crohn's and Colitis 15, Supplement_1 (01.05.2021): S335—S336. http://dx.doi.org/10.1093/ecco-jcc/jjab076.431.
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Abstract Background In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn’s disease (CD) on ustekinumab achieved endoscopic response and 10.9% achieved endoscopic remission at week (w)44. We aimed to investigate if improved endoscopic outcomes can be achieved through dose optimisation based on a population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis. Methods Real-world data were obtained from 83 patients with moderate-to-severe CD (94% multi-refractory) enrolled in a prospective cohort study receiving ustekinumab 6 mg/kg induction and every eight-week (q8w) 90 mg maintenance therapy. Ustekinumab serum concentrations were measured at mid-dose (w4) and trough (w8, w16, w24). Faecal calprotectin (fCal) was measured at baseline and at w4, w8, w16, w24. Endoscopic response (≥50% decrease in simple endoscopic score for CD [SES-CD]) and endoscopic remission (SES-CD ≤2) were assessed at w24. Modelling and simulation were performed using NONMEM 7.4. Results Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fCal, and a logistic regression popPD model linking fCal at w8 to endoscopic outcomes at w24 (Figure 1). Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. The terminal half-life of ustekinumab in a median patient (bodyweight 65 kg, serum albumin 42.7 g/L) was 20.4 days. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1,800 μg/g to 694 μg/g (Figure 2a) The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1,800 μg/g to 214 μg/g (Figure 2b).The results from the simulation-based comparison of q8w and q4w maintenance dosing are shown in Table 1. Dose doubling (180 mg q8w), as opposed to interval halving (90 mg q4w), was predicted to result in a ustekinumab trough concentration of 2.4 μg/mL instead of 4.8 μg/mL. Conclusion The developed model can guide clinical trial design and support model-informed dose optimisation to improve endoscopic outcome rates. Although our analyses showed that q4w dosing resulted in higher ustekinumab and lower fCal concentrations, the proportion of patients achieving endoscopic remission was limited.
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Stroh, Mark, Rachel Li, Hong Lu, Russ Wada, Jennifer Hope Richardson, John W. Frye und Amy C. Peterson. „Preliminary clinical pharmacokinetics and dose-response to support a phase II dose selection for CX-2009: A masked probody drug conjugate to CD166.“ Journal of Clinical Oncology 38, Nr. 15_suppl (20.05.2020): 3599. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3599.
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3599 Background: PROBODY therapeutics are antibody prodrugs with cleavable peptide masks designed to reduce off-tumor, on-target toxicities. The mask blocks binding in the periphery and is removed by tumor-associated proteases resulting in intratumoral binding. CX-2009 is a PROBODY drug conjugate directed against CD166/ALCAM, which is a target overexpressed in carcinomas but not suitable for traditional ADC targeting because it is expressed in normal epithelium. CX-2009 is conjugated to DM4, a potent microtubule inhibitor. Here we report preliminary clinical pharmacokinetic (PK) and exploratory dose-response (DR) analyses for CX-2009 from the ongoing phase 1/2 PROCLAIM-CX-2009 study (NCT03149549). Methods: Human PK and anti-drug antibody (ADA) data were obtained at selected times post-dose following IV 0.25–10 mpk CX-2009 Q3W and of 6 mpk Q2W. Covariates were selected for population PK (POPPK) based on multivariate screening at P< 0.01. Preliminary exploratory DR analyses were conducted for selected endpoints including adverse events of special interest and response data (CR, PR, SD, and PD). Results: Preliminary CX-2009 PK data from 92 subjects were available as of October 2019. Median free DM4 levels circulated at ≤0.3% of Total CX-2009 (masked + activated CX-2009) levels across the 1–10 mpk dose levels. A two-compartment POPPK model with linear elimination was fit to the Intact (masked form) CX-2009 data. The preliminary CX-2009 POPPK model estimates for Intact CX-2009 clearance (CL), volume of distribution, and half-life were 0.47 L/day, 4.51 L, and 7.14 days, respectively, with 91% of CX-2009 circulating as Intact CX-2009. ADA was not a statistically significant covariate on Intact CX-2009 CL. Evidence of clinical activity was observed at doses of 4 mpk Q3W or higher. DR analysis suggested that the frequency of grade ≥3 ocular toxicity events increased significantly at dose equivalents ≥8 mpk Q3W. POPPK simulations suggested that the targeted 90 nM trough concentration (based on nonclinical data) would be contained within the 90% prediction interval of predicted Intact CX-2009 levels following CX-2009 7 mpk. Conclusions: Preliminary CX-2009 PK data following CX-2009 0.25-10 mpk suggest that CX-2009 circulates predominantly as Intact CX-2009, and that Intact CX-2009 PK is not strongly influenced by target-mediated drug disposition or ADA. Preliminary DR and POPPK simulations support further evaluation of 7 mpk CX-2009 Q3W in selected cohort expansions. Clinical trial information: NCT03149549 .
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Stroh, Mark, Michelle Green, Bjorn L. Millard, William Garner, Hong Lu, Jennifer Hope Richardson und Alison L. Hannah. „Preliminary population pharmacokinetics supports phase II dose selection for masked anti-PD-L1 antibody CX-072.“ Journal of Clinical Oncology 38, Nr. 15_suppl (20.05.2020): 3602. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3602.
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3602 Background: PROBODY therapeutics (Pb-Tx) are antibody prodrugs designed to reduce off-tumor, on-target toxicities. The mask inhibits Pb-Tx binding in the periphery yet can be removed by tumor-associated proteases, restricting target engagement to the tumor. This is the first report of preliminary clinical pharmacokinetic (PK) analysis supporting selection of the phase II dose for CX-072, an anti–PD-L1 Pb-Tx, from the ongoing phase I/II PROCLAIM-CX-072 study (NCT03013491). Methods: A quantitative systems pharmacology (QSP) model1 was used to project the CX-072 plasma trough level (Cmin) corresponding to 95% intratumoral receptor occupancy (RO). Human PK and anti-drug antibody (ADA) data were obtained at selected times postdose following IV administration of 0.03–30 mpk CX-072 in PROCLAIM-CX-072. Population PK (POPPK) modeling was performed with NONMEM v7.3.0. Exploratory analysis and simulations were done with R v3.3.1 or later. Covariates were selected for POPPK using forward addition ( P<0.05) followed by backward deletion ( P<0.01). Results: The preliminary POPPK analyses were informed using available PK data as of August, 2019 from 135 subjects receiving CX-072 Q2W as monotherapy in the dose-escalation and expansion cohorts of PROCLAIM-CX-072. A mixture model was used to capture time- and dose-dependent apparent ADA effect on clearance (CL). The preliminary POPPK model estimates for CX-072 CL and volume of distribution (Vd) were 0.306 L/day and 4.84 L, respectively. Statistically significant covariate effects included body weight on the central Vd and CL, and albumin on CL. The QSP model predicted a CX-072 Cmin of 13–99 nM would be required for 95% intratumoral RO. POPPK simulations suggested that >95% of patients receiving CX-072 10 mg/kg Q2W would meet or exceed this targeted Cmin regardless of ADA. Additional observed data indicated that the majority of patients receiving 10 mpk CX-072 Q3W × 4 with 3 mpk ipilimumab (IPI) Q3W × 4 in the CX-072-IPI combination part of PROCLAIM-CX-072 maintained the targeted Cmin. Simulations did not suggest there would be a clinically meaningful change in exposure following a fixed dose of CX-072 800 mg relative to the 10 mpk weight-based dose. Conclusions: Preliminary PK analysis supports selection of 800 mg CX-072 Q2W as the recommended monotherapy dose and 800 mg Q3W when combined with IPI. The combination of 800 mg CX-072 + 3 mpk IPI Q3W × 4 doses, followed by monotherapy administration of 800 mg CX-072 Q2W is being further explored in phase II. Reference: 1) Stroh M et al. CPT. 2019(9):676-84. Clinical trial information: NCT03013491 .
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Yee, Ka Lai, Huub Jan Kleijn, Thomas Kerbusch, Randolph P. Matthews, Mary Beth Dorr, Kevin W. Garey und Rebecca E. Wrishko. „Population Pharmacokinetics and Pharmacodynamics of Bezlotoxumab in Adults with Primary and Recurrent Clostridium difficile Infection“. Antimicrobial Agents and Chemotherapy 63, Nr. 2 (19.11.2018): e01971-18. http://dx.doi.org/10.1128/aac.01971-18.
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ABSTRACT The fully human monoclonal antibody bezlotoxumab is indicated for preventing the recurrence of Clostridioides difficile (formerly Clostridium difficile) infection (CDI) in adults who receive antibacterial treatment for CDI and who are at high risk for a CDI recurrence. The efficacy and safety of 10-mg/kg of body weight bezlotoxumab were demonstrated in two phase 3 trials: the MODIFY I (ClinicalTrials.gov registration number NCT01241552) and MODIFY II (ClinicalTrials.gov registration number NCT01513239) trials. Here, a population pharmacokinetic (popPK) analysis, performed using data from the MODIFY I and II trials (n = 1,515) and from three phase 1 trials (n = 72) to characterize bezlotoxumab pharmacokinetics (PK) in phase 3 clinical trial participants and in healthy subjects, is reported. A stepwise covariate search was conducted to identify factors influencing PK. Post hoc-estimated bezlotoxumab exposures from the popPK model were used to conduct an exposure-response analysis for CDI recurrence. Bezlotoxumab PK were described by a two-compartment model with linear elimination and allometric scaling for clearance and the volume of distribution by body weight. Although the final popPK model included gender, ethnicity (Japanese descent), race (black versus nonblack), and albumin level as significant covariates, the impact of these factors was not clinically meaningful, based on the totality of the PK and clinical experience. Exposure-response analysis of CDI recurrence demonstrated a similar low rate of CDI recurrence over the entire range of exposures achieved in the phase 3 trials, indicating that exposures were on the maximal response plateau of the exposure-response curve. Overall, the analyses confirmed the appropriateness of the 10-mg/kg dose across the phase 3 trial population with no dose adjustments necessary over a broad demographic background.
Dissertationen zum Thema "PopPK"
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Zimmermann, Estevan Sonego. „Modelagem farmacocinética populacional na avaliação do papel da glicoproteína-P na penetração tecidual de fluoroquinolonas“. reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/163764.
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Objetivos: O objetivo deste trabalho foi desenvolver modelo farmacocinético (popPK) populacional para descrever simultaneamente as concentrações das fluoroquinolonas (levofloxacino – LEV e ciprofloxacino – CIP) no plasma, pulmão e próstata na presença e ausência do inibidor da P-gp tariquidar (TAR) visando determinar a contribuição desse transportador de efluxo na distribuição tecidual desses antimicrobianos. Método: Para alcançar este objetivo as seguintes etapas foram realizadas: i) foi validado o método analítico de HPLC-fluorescência para quantificação de CIP em amostras de plasma e microdialisado; ii) foram estabelecidas as condições para microdiálise para o CIP e as taxas de recuperação in vitro, por diálise e retrodiálise, e em tecido pulmonar e prostático in vivo por retrodiálise; iii) foi avaliada a farmacocinética do LEV após administração a ratos Wistar via i.v. bolus e por nebulização intratraqueal na dose de 7mg/kg na ausência e após administração prévia de TAR (15 mg/Kg i.v.); iv) foi desenvolvido um modelo popPK para prever as concentrações do LEV simultaneamente no plasma, pulmão e próstata após administração intravenosa e intratraqueal na presença e ausência do TAR; v) foi desenvolvido o modelo popPK para descrever as concentrações de CIP simultaneamente no plasma, pulmão e próstata após administração a ratos Wistar da dose de 7 mg/kg i.v. bolus na presença e ausência de TAR (15 mg/kg i.v.); vi) Para ambos os fármacos os dados foram avaliados por análise não-compartimental e modelados por modelo de quatro compartimentos modificado, com ajuda do software NONMEN®. Resultados e Conclusões. i) Método analítico foi desenvolvido e validado com sucesso para quantificação de CIP em HPLC/fluorescência mostrando-se linear na faixa de 10–2000 ng/mL em plasma e 5–1000 ng/mL em microdialisado com coeficientes de determinação (r2) superiores a 0,99. Os valores obtidos de erro padrão relativo para ensaios de precisão intra e inter-dia foram entre 8,8 e 6,0 %, para microdialisado entre 11,1 e 7,4 % para plasma, respectivamente. Os valores de exatidão foram 86,1% entre 114.3% para microdialisado e 85,6% entre 108,2% para plasma; ii) A avaliação do CIP por microdiálise mostrou recuperação concentração independente (0,25 - 1,5 μg/mL). Além disso, não houve diferença entre as recuperações obtidas por diálise e retrodiálise para o mesmo fluxo. No fluxo selecionado para os experimentos (1,5 μL/min) as recuperações médias por diálise e retrodiálise foram 23,0 ± 2,8% e 22,8 ± 1,6 %, respectivamente. A recuperação relativa das sondas in vivo foi de 11,3 ± 1,9 e 13,1 ± 2,7 % para pulmão e próstata, respectivamente; iii) A análise dos perfis plasmáticos e teciduais LEV após dose intravenosa do grupo controle (sem TAR) mostrou boa penetração tecidual na próstata (ƒT = 0,68) e no pulmão (ƒT = 0,69). Para a mesma via de administração, o grupo TAR mostrou uma penetração praticamente inalterada para o pulmão (ƒT = 0,81) e um aumento de mais de 2 vezes na penetração prostática (ƒT= 1,64). Na dose intratraqueal houve um aumento significativo na biodisponibilidade para o grupo TAR (F = 0,86) em relação ao controle (F = 0,4). Nessa via de administração foi detectado um aumento significativo na exposição (ASC) do pulmão ao LEV no grupo TAR demonstrando que o transporte por efluxo no pulmão é mais relevante quando o fármaco é administrado pela via intratraqueal; iv) Para o LEV, o modelo popPK de quatro compartimentos foi capaz de descrever simultaneamente os dados no plasma, pulmão e próstata na presença e ausência do TAR. Além disso, o modelo para administração intravenosa foi estendido e adaptado para administração intratraqueal. Foi possível analisar o impacto do transporte por efluxo sobre a penetração tecidual do LEV por diferentes vias de administração utilizando o modelo popPK; v) A avaliação do perfil farmacocinético plasmático do CIP após administração intravenosa, na presença e ausência de TAR, demonstrou diferença significativa entre todos os parâmetros calculados por análise não-compartimental, exceto para a constante de velocidade de eliminação (= 0,05). Em relação à penetração tecidual do CIP na próstata e pulmão, não houve alteração significativa nos parâmetros de eliminação e exposição tecidual do fármaco na presença do inibidor de efluxo TAR ( = 0,05), demonstrando que o transporte por efluxo possui papel minoritário no processo de distribuição do fármaco para os tecidos estudados. O modelo popPK de quatro compartimentos foi capaz de descrever as concentrações plasmáticas totais, livres no pulmão e próstata em presença e ausência de TAR, simultaneamente; vi) O modelo popPK desenvolvido permitiu o estudo mais profundo do processo de distribuição do LEV e do CIP no pulmão e próstata.Objectives: The aim of this study was to develop a population pharmacokinetic model (popPK) able to simultaneously describe fluoroquinolones (levofloxacin – LEV and ciprofloxacin – CIP) concentrations in plasma, lung and prostate in the presence and absence of the inhibitor of P-gp tariquidar (TAR) to determine the contribution of this efflux transporter on the tissue distribution of these antimicrobials. Methods: To achieve this goal the following steps were taken: i) An analytical method by HPLC-fluorescence was developed and validated for CIP analysis in plasma and microdialysate samples; ii) microdialysis conditions were established for CIP including determination of in vitro relative recovery by dialysis and retrodialysis. The relative recovery was also determined in vivo, in lung and prostate, by retrodialysis; iii) LEV pharmacokinetics was evaluated after intravenous (i.v.) bolus and intratracheal (i.t.) administration of 7 mg/kg dose alone and following TAR administration (15 mg/kg i.v.) to Wistar rats; iv) a popPK model was developed to describe and predict LEV concentrations in plasma, lung and prostate following i.v. and i.t. dosing with and without TAR co-administration; v) the popPK model developed was used to describe CIP concentrations in plasma, lung and prostate after i.v. bolus administration of 7 mg/kg in presence and absence of TAR; vi) For both drugs non-compartmental analysis was performed besides data modeling by four compartment model using NONMEN®. Results and Conclusions i) The analytical method was developed and successfully validated for quantification of CIP by HPLC/fluorescence. The method was linear in the range of 10-2000 ng/mL in plasma and 5-1000 ng/mL in tissues microdialysate samples with coefficients of determination (r2) higher than 0.99. The relative standard error (RSD) obtained for intra and inter-day precision were lower than 8.8% and 6.0% for microdialysate and lower than 11.1 and 7.4% for plasma, respectively. The accuracy was 86.1% to 114.3% for microdialysate and 85.6 to 108.2 % for plasma samples; ii) the evaluation of CIP microdialysis probes relative recovery in vitro showed that the recovery was concentration independent (0.25 to 1.5 μg/mL). In addition, there was no statistical difference between the recoveries determined by dialysis and retrodialysis at the same flow rate. Using the selected flow rate (1.5 μL/min) the recoveries by dialysis and retrodialysis were 23.0 ± 2.8% and 22.8 ± 1.6%, respectively. CIP relative recoveries in vivo by retrodialysis were 11.3 ± 1.9 and 13.1 ± 2.7% for lung and prostate, respectively; iii) the analysis of LEV plasma and tissues concentration-time profiles after i.v. dosing showed a good tissue penetration of LEV in the prostate (ƒT = 0.68) and lung (ƒT = 0.69). For the same route of administration, TAR group showed virtually the same penetration into lung (ƒT = 0.81) and an increase of over 2 fold in drug levels in prostate (ƒT = 1.64). For the i.t. dose, there was a significant increase on LEV bioavailability for TAR group (F = 0.86) compared to control (F = 0.4). Furthermore, a significant increase was detected on lung exposure to LEV for TAR group indicating that efflux transport in the lung is more relevant when the drug is administered by the i.t. route; iv) For LEV, a four compartment model was able to describe the data simultaneously in plasma, lung and prostate in the presence and absence of TAR. Moreover, the intravenous model was extended to adapt the intratracheal dosing route. The popPK model allowed to analyze the impact of efflux transport on tissue LEV penetration of different routes of administration; v) the evaluation of plasma CIP profiles after i.v. dosing with and without TAR showed a significant difference in all parameters determined by non-compartmental analysis in the TAR group, except the elimination rate constant (α = 0.05). The CIP tissue penetration in prostate and lung, no significant difference was observed in tissues exposure and elimination rate when TAR was present demonstrating that efflux transporter play a minor role on CIP distribution to tissues investigated (α = 0.05). The popPK model with four compartments was able to describe CIP concentrations in plasma, lung and prostate in the presence and absence of TAR, simultaneously; vi) the popPK model developed allowed a more detailed investigation of LEV and CIP distribution process in lung and prostate.
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Bernardi, Priscila Martini. „Avaliação por microdiálise da penetração pulmonar da tobramicina em modelo de pneumonia por microrganismo formador de biofilme“. reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/149491.
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Objetivo: Avaliar a influência da infecção por Pseudomonas aeruginosa formadora de biofilme na penetração pulmonar da tobramicina através da modelagem populacional dos dados de plasma e microdialisado em animais sadios e infectados. Metodologia: A pneumonia foi desenvolvida através de inoculação de P. aeruginosa (cepa PA14) pela via intratraqueal (109 UFC/mL) a ratos Wistar. Sete dias após a inoculação os animais infectados (n = 5) receberam tobramicina 10 mg/kg i.v. bolus. Animais saudáveis (n = 6) foram utilizados como controle. As concentrações livres pulmonares foram coletadas por microdiálise (sonda CMA/20). As sondas de microdiálise foram calibradas in vitro através de diálise e retrodiálise e in vivo utilizando retrodiálise. A ligação da tobramicina às proteínas plasmáticas foi determinada por microdiálise. As concentrações do fármaco nas amostras foram determinadas por cromatografia líquida em tandem com espectrometria de massas (CLAE-EM/EM) utilizando metodologia validada. Os parâmetros farmacocinéticos foram determinados por abordagem não-compartimental (Phoenix®) e modelagem populacional (popPK) (Monolix®). Resultados e Discussão: A recuperação relativa (RR) das sondas foi independente da concentração de tobramicina e inversamente proporcional ao fluxo de perfusão. A RR determinada in vivo foi de 27,64 % ± 7,70 para animais sadios e 24,47 % ± 1,66 para animais infectados. A ligação às proteínas plasmáticas foi de 11,3 ± 1,9%. A infecção com formação de biofilme não alterou a farmacocinética plasmática da tobramicina, entretanto reduziu em cerca de 70% a penetração pulmonar do fármaco. As concentrações plasmáticas e teciduais foram simultaneamente descritas por um modelo farmacocinético populacional de dois compartimentos, tanto em animais sadios como infectados. A infecção, utilizada como covariável categórica, permitiu descrever as alterações no volume do compartimento periférico e na constante de eliminação do compartimento central devido à infecção. Conclusões: As concentrações plasmáticas da tobramicina, utilizadas para ajuste posológico, superestimam as concentrações ativas no pulmão infectado. O modelo popPK descrito permite a previsão das concentrações livres pulmonares da tobramicina em pulmão infectado, podendo auxiliar na otimização da terapia de pneumonias com P. aeruginosa formadora de biofilme.Objective: To evaluate the influence of biofilm-forming Pseudomonas aeruginosa infection on tobramycin lung penetration by population pharmacokinetic modeling of plasma and microdialysate data in healthy and infected rats. Methodology: The infection was developed by intratracheal inoculation (109 CFU/mL) of P. aeruginosa (PA14 strain) to Wistar rats. In order to determine plasma and tissue concentrations, seven days after the inoculation the infected animals (n = 5) received tobramycin 10 mg/kg i.v. bolus dose via femoral vein. A healthy group (n = 6) was used as control. Free lung concentrations were determined in microdialysate samples obtained using CMA/20 probes. Microdialysis probes were calibrated in vitro by dialysis and retrodialysis and in vivo by retrodialysis. Tobramycin plasma protein binding was determined by microdialysis. Plasma and tissue concentrations were quantified by a developed and validated liquid chromatography in tandem with mass spectrometry (LC-MS/MS) method. Compartmental and non-compartmental analyses were carried out by Monolix™ and Phoenix™ software, respectively. Results and Discussion: Microdialysis probes relative recovery was independent of the tobramycin concentration and is inversely proportional to the perfusion flow rate investigated. The in vivo probe recovery was 27.64 % ± 7.70 (healthy rats) and 24.47 % ± 1.66 (infected rats). The plasma protein binding was 11.3 ± 1.9%. The biofilm-forming lung infection did not alter tobramycin plasma pharmacokinetics, however, reduced lung penetration in about 70%. The plasma and tissue concentrations-time profiles were simultaneously described by a two compartment popPK model in healthy and infected animals. The infection process, used as categorical covariate allowed describing the changes observed in the volume of the peripheral compartment and in constant rate of elimination from the central compartment. Conclusions: Tobramycin plasma concentrations, used for dosing adjustments, overestimate active concentrations in infected lung. The described popPK model allows predicting free tobramycin lung concentrations in infected lung and could be useful to optimize the treatment of pneumonia caused by biofilm-forming P. aeruginosa with this drug.
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Torres, Bruna Gaelzer Silva. „Modelagem farmacocinética/farmacodinâmica (PK/PD) para caracterização do efeito do ciprofloxacino em infecções com biofilmes de Pseudomonas aeruginosa“. reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/159488.
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Biofilmes são comunidades bacterianas complexas encapsuladas em matrizes poliméricas autoproduzidas e podem se desenvolver em superfícies inertes ou tecidos vivos. A formação do biofilme é um importante fator de virulência, pois permite à bactéria resistir às respostas do hospedeiro e à terapia antimicrobiana. Devido a essa elevada resistência aos antimicrobianos, é difícil estabelecer uma estratégia eficaz para o tratamento de infecções com formação de biofilmes, levando a falhas na erradicação das mesmas. Nesse contexto, o objetivo do presente estudo é desenvolver um modelo farmacocinético/farmacodinâmico (PK/PD) para descrever o efeito do ciprofloxacino (CIP) na presença de biofilmes de Pseudomonas aeruginosa (ATCC 27853), visto que a modelagem PK/PD de antimicrobianos é uma ferramenta útil na escolha de regimes posológicos que atinjam o efeito bactericida máximo, minimizando o desenvolvimento de resistência. Para atingir esse objetivo, inicialmente um método analítico por CLAE/fluorescência foi desenvolvido para quantificar o CIP em amostras de plasma e microdialisado. O método desenvolvido foi simples, rápido e com sensibilidade adequada para corretamente caracterizar a farmacocinética plasmática e pulmonar do CIP. Posteriormente, um modelo animal de infecção pulmonar crônica foi adaptado da literatura e padronizado, permitindo a investigação da distribuição pulmonar do CIP em ratos Wistar sadios e infectados. Para tal, bactérias foram imobilizadas em beads de alginato a fim de manter a infecção por até 14 dias com cargas bacterianas superiores à 108 UFC/pulmão. Estudo de microdiálise foi então conduzido para avaliar as concentrações livres de CIP após administração intravenosa de 20 mg/kg. A análise não-compartimental (NCA) e a modelagem farmacocinética populacional (PopPK) dos dados foram realizadas nos softwares Phoenix® e NONMEM®, respectivamente. Diferenças significativas foram observadas no clearance plasmático (1,59 ± 0,41 L/h/kg e 0,89 ± 0,44 L/h/kg) e na constante de eliminação (0,23 ± 0,04 h-1 e 0,14 ± 0,08 h-1) para ratos sadios e infectados, resultando em uma exposição plasmática maior nos animais infectados (ASC0-∞ = 27,3 ± 12,1 μg·h/mL) quando comparados com os animais sadios (ASC0-∞ = 13,3 ± 3,5 μg·h/mL) ( = 0,05). Apesar da maior exposição plasmática, quando comparados com os animais saudáveis (fT = 1,69), animais infectados apresentaram uma penetração pulmonar quatro vezes menor (fT = 0,44). Diferenças na constante de eliminação pulmonar não foram observadas. Dados plasmáticos e pulmonares foram simultaneamente descritos por modelo PopPK constituído de compartimentos venoso e arterial, dois compartimentos representativos de duas regiões pulmonares distintas e dois compartimentos periféricos, representando outros tecidos que não os pulmões. Um clearance pulmonar foi adicionado ao modelo apenas para os dados de microdiálise dos animais infectados (CLlung = 0,643 L/h/kg) afim de explicar a exposição tecidual diminuída. O modelo desenvolvido descreveu, com sucesso, os dados plasmáticos e teciduais de animais sadios e infectados, permitindo a correta caracterização das alterações observadas na disposição plasmática e pulmonar do CIP decorrentes da infecção com biofilme. Para os estudos de farmacodinâmica, o efeito bactericida do CIP frente a biofilmes e células planctônicas de P. aeruginosa foi simultaneamente avaliado através do uso de curvas de morte bacteriana. Para a construção destas curvas, biofilmes de P. aeruginosa foram formados na superfície de blocos de acrílico e sua formação foi confirmada pelo ensaio cristal violeta e por microscopia eletrônica de varredura. Os blocos foram expostos a concentrações constantes de CIP (de 0,0625 a 10 μg/mL) e, em tempos pré-determinados, células planctônicas e de biofilmes eram amostradas para quantificação. Um modelo semi-mecanístico que incorpora um modelo Emax sigmoidal foi utilizado para descrever o efeito do CIP frente a ambos estilos de vida bacteriano. Uma subpopulação pré-existente com menor suscetibilidade ao CIP foi incluída no modelo e o efeito do CIP nesta subpopulação também foi descrito pelo modelo Emax sigmoidal. A comparação dos parâmetros estimados pelo modelo demonstrou que o efeito in vitro do CIP é maior para as células planctônicas (EC50 = 0,259 mg/L e 0,123 mg/L e Emax = 2,25 h-1 e 5,59 h-1 para biofilmes e planctônicas, respectivamente). A potência estimada do CIP para a subpopulação resistente foi muito menor para ambos estilos de vida bacteriano (EC50 = 2,71 mg/L e 1,15 mg/L para biofilmes e planctônicas, respectivamente). Os modelos desenvolvidos podem ser utilizados para a simulação de cenários não testados e servir como uma ferramenta para guiar a escolha dos regimes posológicos adequados, contribuindo para o sucesso terapêutico no tratamento de infecções associadas à biofilmes.Biofilms are complex bacterial communities enclosed in self-produced polymeric matrices that can develop in inert surfaces or living tissues. Biofilm formation is an important virulence factor that allows bacteria to resist host responses and antibacterial agents. Due to this high resistance to antibiotics, it is difficult to establish an efficacious strategy for treatment of infections with biofilm formation leading to failure in infection eradication. In this context, the goal of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the antimicrobial effect of ciprofloxacin (CIP) in the presence of biofilms of Pseudomonas aeruginosa (ATCC 27853), since PK/PD modeling for antibacterial agents can be a useful tool to choose dosing regimens and to achieve the maximum bactericidal effect, minimizing the development of resistance. To reach this goal, firstly an analytical method based on HPLC/fluorescence was developed in order to quantify CIP in plasma and lung microdialysate. The developed method was simple, fast and with enough sensibility to proper characterize CIP plasma and lung pharmacokinetics. Secondly, an animal model of chronic lung infection was adapted from literature and standardized, allowing the analysis of CIP lung distribution in infected and healthy Wistar rats. Bacteria were immobilized in alginate beads prior to inoculation to Wistar rats in order to sustain the pneumonia for 14 days, maintaining a bacterial load superior to 108 CFU/lung. A microdialysis study was then conducted to evaluate free CIP concentrations after an intravenous administration of 20 mg/kg. Non-compartimental analysis (NCA) and populational PK modeling (PopPK) of the data were performed in Phoenix® and NONMEM®, respectively. Statistical differences were observed in the plasma clearance (1.59 ± 0.41 L/h/kg and 0.89 ± 0.44 L/h/kg) and elimination rate constant (0.23 ± 0.04 h-1and 0.14 ± 0.08 h-1) for healthy and infected rats, respectively, resulting in a significantly higher CIP plasma exposure in infected rats (AUC0-∞ = 27.3 ± 12.1 μg·h/mL) compare to healthy animals (AUC0-∞ = 13.3 ± 3.5 μg·h/mL) ( = 0.05). Besides the plasma exposure, a four times lower pulmonary penetration was observed in infected rat’s lungs (fT = 0.44) in comparison to healthy animals (fT = 1.69), with no significant differences in the lung elimination rate constant. Plasma and lung data were simultaneously fitted using a PopPK model consisting of an arterial and a venous compartment, two compartments representing different regions of the lungs and two peripheral distribution compartments, representing tissues other than lungs. A lung clearance was added to the model for infected animals (CLlung = 0.643 L/h/kg) to explain the lower tissue exposure. The model successfully described the plasma and microdialysis data from both, healthy and infected rats and allowed to correctly describe the changes in CIP plasma and lung disposition in biofilm infections. For the pharmacodynamic studies, CIP bactericidal effect against Pseudomonas aeruginosa biofilms and planktonic shedding cells were simultaneously evaluated using the time-kill curves approach. For the time-kill curves construction, P. aeruginosa biofilms were formed in acrylic blocks, which was confirmed by the crystal violet assay and scanning electron microscopy. The blocks were placed in flasks containing Mueller-Hinton growth medium and exposed to constant CIP concentrations (ranging from 0.0625 to 10 μg/mL). At pre-determined time points, biofilm and planktonic cells were sampled for bacterial counting. A mechanism-based model which incorporates a sigmoidal Emax model was used to describe the CIP effect against P.aeruginosa in both llifestyles, biofilm and planktonic. The presence of a pre-existing resistant subpopulation was included in the model and also modeled with a sigmoidal Emax model to describe CIP effect in this subpopulation. Comparison of the parameter estimates showed that the in vitro effect of CIP is higher for planktonic cells (EC50 = 0.259 mg/L and 0.123 mg/L and Emax = 2.25 h-1 and 5.59 h-1 for biofilm and planktonic cells, respectively). CIP potency was much lower for the resistant subpopulation, for both bacteria lifestyles (EC50 = 2.71 mg/L and 1.15 mg/L for biofilm and planktonic, respectively). The developed models can be used to simulate untested scenarios and serve as a tool to guide dosing regimen selection, contributing for the therapeutic success of treatments of biofilm-associated infections.
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Bicchierai, Marco. „Ai confini della Repubblica di Firenze : Poppi dalla Signoria dei Conti Guidi al vicariato del Casentino /“. Firenze : Leo S. Olschki, 2005. http://catalogue.bnf.fr/ark:/12148/cb40071465v.
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Dediu, Igorevna. „Tall Poppy Syndrome and its effect on work performance“. Thesis, University of Canterbury. Psychology, 2015. http://hdl.handle.net/10092/10261.
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The aim of this study was to find out whether employees would perform worse if they perceived their work colleagues to have negative attitudes towards tall poppies (colleagues favoured the fall of tall poppies rather than rewarding tall poppies), thus displaying typical tall poppy syndrome perceptions. Performance measures were: decision-making vigilance, decision-making dependence, decision-making avoidance, problem solving, creativity, service quality, and the personality construct need for affiliation. Control variables were age, tenure and need for achievement. The design of the study was cross-sectional, online surveys were used to collect the data. The link to the survey was distributed using LinkedIn groups and Facebook advertising, yielding a sample of 229 participants. The data was analysed using regression; the results confirmed 3 of the 7 hypotheses. The results indicated that employees working in an environment that favoured the fall of tall poppies, showed lower decision-making dependability and higher decision-making avoidance. Internal service quality was partially confirmed, it was negatively associated with participants working in an environment that favoured the fall of tall poppies, rather than reward; Theories about the contribution New Zealand’s history has made to the development of tall poppy syndrome are considered. Practical implications of the results are discussed. Directions for future studies in industrial and organizational psychology on the effects of tall poppy syndrome on work performance are discussed.
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Giovannetti, Alessandra. „Francesco Morandini detto il Poppi /“. Firenze : EDIFIR, 1995. http://catalogue.bnf.fr/ark:/12148/cb37521462h.
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Leding, Albin. „Recommendation for first pharmacokinetic in vivo experiment design with a pharmacometric informed approach“. Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-447311.
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Tuberculosis, the leading cause of death by a single infection disease caused by bacteria, requires long treatments and the bacteria are prone to develop drug resistance. Therefore, new efficient treatment regiments needs developing, which requires new tools for drug development. A major reason for discontinuance of a drug under development is undesired pharmacokinetic properties. Therefore, it is important to have early information of this, preferably the first time the drug is tested in animals. The first in vivo pharmacokinetic experiment is often done in mice and the only information present at this stage are often in vitro values and physicochemical properties. Physiological-based pharmacokinetic modelling can be used to extrapolate from in vitro to in vivo values. From this, the first in vivo pharmacokinetic experiment can be designed, often with the goal of reducing the amount of mice. This goal is one of the three R.s and it is called Reduction. To explore the Reduction of an experiment population pharmacokinetic modelling can be utilized via exploration of the imprecision, bias and probability of an informative experiment to evaluate if a design meets the goal of Reduction. In this report a recommendation of the first in vivo pharmacokinetic experiment is presented. This is based on in vitro values and physicochemical properties that are common in anti-tuberculosis drugs. If the probability of an informative experiment is critical, a terminal sampling of 40 mice is recommended. If imprecision and bias are necessary, zipper sampling of 10 mice is recommended.
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Leding, Albin. „Optimized design recommendation for first pharmacokinetic in vivo experiments for new tuberculosis drugs using pharmacometrics modelling and simulation“. Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-447311.
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Tuberculosis, the leading cause of death by a single infection disease caused by bacteria, requires long treatments and the bacteria are prone to develop drug resistance. Therefore, new efficient treatment regiments needs developing, which requires new tools for drug development. A major reason for discontinuance of a drug under development is undesired pharmacokinetic properties. Therefore, it is important to have early information of this, preferably the first time the drug is tested in animals. The first in vivo pharmacokinetic experiment is often done in mice and the only information present at this stage are often in vitro values and physicochemical properties. Physiological-based pharmacokinetic modelling can be used to extrapolate from in vitro to in vivo values. From this, the first in vivo pharmacokinetic experiment can be designed, often with the goal of reducing the amount of mice. This goal is one of the three R.s and it is called Reduction. To explore the Reduction of an experiment population pharmacokinetic modelling can be utilized via exploration of the imprecision, bias and probability of an informative experiment to evaluate if a design meets the goal of Reduction. In this report a recommendation of the first in vivo pharmacokinetic experiment is presented. This is based on in vitro values and physicochemical properties that are common in anti-tuberculosis drugs. If the probability of an informative experiment is critical, a terminal sampling of 40 mice is recommended. If imprecision and bias are necessary, zipper sampling of 10 mice is recommended.
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Day, Keith B. „Papaver somniferum and P. bracteatum : tissue culture and morphinan alkaloid production“. Thesis, University of Leicester, 1987. http://hdl.handle.net/2381/35449.
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Papaver somniferum plants accumulate the secondary products codeine and morphine. P. bracteatum accumulates their precursor, thebaine. The aims of the project were to use tissue cultures for the production of these alkaloids and for the biotransformation of thebaine to codeine and morphine. Methods were evaluated for the extraction, separation and quantification of mg or mug amounts of morphinan alkaloids from plant material. TLC, IIPLC and RIA were useful. Poppy cells fron a range of seed sources and explants were grown in static and suspension culture. Manipulations were made in atterpts to induce morphinan biogenesis. These included inmobilisation of cells and changes in the growth medium. Morphinans were absent from unspecialised cells in all but one instance. The biotransformation of thebaine was tested in cell suspensions of P. somniferum and Nicotiana alata. Using thebaine (biosynthesised from CO2) these experiments were extended to organs of the P. somniferum plant. A thebaine-biotransfomation product arose in N. alata (but not P. somniferum) suspensions that also arose in excised P. somniferum capsules. A non-specific enzymic activity is proposed. No codeine or morphine were produced. Plant regeneration was demonstrated, in good yield, by embryogenesis fron meristenoid tissue of P. bracteatum. In P. somniferum the process was initiated but was not routinely successful. Regeneration may be useful for plant improvenent via cloning or as a source of variation. On reorganisation into plantlets, capacity for morphinan alkaloid accumulation was realised. Capacity for alkaloid accumulation is discussed in tenns of a requisite minimum level of cytodifferentiation, perhaps of laticifer-like cells. The uptake or binding of radiolabelled morphine by suspension cultures was investigated, since binding may be a reason for failure to detect morphinans in cultures extracted by the usual methods. Evidence was found that exogenous morphine binds to an insoluble fraction in P. somniferum and I. tabacum but cells did not contain any endogenous bound morphincins.
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Techapinyawat, Rheana. „The Evolution of Opium and Anesthesia: From the Ancient Sumerians to 1800s“. The University of Arizona, 2018. http://hdl.handle.net/10150/626597.
Der volle Inhalt der QuelleBücher zum Thema "PopPK"
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1927-, Nichols Peter, Hrsg. Poppy. London: S. French, 1991.
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2
Avi. Poppy. New York: HarperTrophy, 2001.
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3
Larriva, Barbara. Poppy. New York: Ballantine Books, 1987.
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4
Tremaine, Jennie. Poppy. Bath: Chivers, 1989.
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5
Avi. Poppy. New York: Avon Books, 1997.
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MacCarthy, Patricia. Poppy. New York: Random House, 2007.
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Mary, Hooper. Poppy. London: Bloomsbury, 2014.
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Poppy. London: Piccadilly Press, 1996.
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Modjeska, Drusilla. Poppy. Ringwood, Vic: McPhee Gribble, 1990.
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10
Poppy. London: Simon & Schuster Children's, 2008.
Den vollen Inhalt der Quelle findenBuchteile zum Thema "PopPK"
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Charles, Denys J. „Poppy“. In Antioxidant Properties of Spices, Herbs and Other Sources, 489–93. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4614-4310-0_47.
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Bernáth, Jenö, und Éva Németh. „Poppy“. In Oil Crops, 449–68. New York, NY: Springer New York, 2009. http://dx.doi.org/10.1007/978-0-387-77594-4_15.
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Bährle-Rapp, Marina. „poppy“. In Springer Lexikon Kosmetik und Körperpflege, 441. Berlin, Heidelberg: Springer Berlin Heidelberg, 2007. http://dx.doi.org/10.1007/978-3-540-71095-0_8235.
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Dasborough, Marie T. „Tall Poppy“. In Encyclopedia of Evolutionary Psychological Science, 1–2. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-16999-6_1467-1.
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Dasborough, Marie T. „Tall Poppy“. In Encyclopedia of Evolutionary Psychological Science, 8102–3. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-319-19650-3_1467.
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Kambič, Bojan. „Dal Microscopio alla Poppa“. In Le costellazioni al binocolo, 233–67. Milano: Springer Milan, 2013. http://dx.doi.org/10.1007/978-88-470-2709-1_10.
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Chitty, Julie A., Robert S. Allen und Philip J. Larkin. „Opium Poppy (Papaver somniferum)“. In Agrobacterium Protocols Volume 2, 383–91. Totowa, NJ: Humana Press, 2006. http://dx.doi.org/10.1385/1-59745-131-2:383.
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Sastry, K. Subramanya, Bikash Mandal, John Hammond, S. W. Scott und R. W. Briddon. „Papaver somniferum (Opium poppy)“. In Encyclopedia of Plant Viruses and Viroids, 1719–21. New Delhi: Springer India, 2019. http://dx.doi.org/10.1007/978-81-322-3912-3_655.
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Baser, Kemal Hüsnü Can, und Neset Arslan. „Opium Poppy (Papaver somniferum)“. In Medicinal and Aromatic Plants of the World, 305–32. Dordrecht: Springer Netherlands, 2014. http://dx.doi.org/10.1007/978-94-017-9276-9_17.
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Sastry, K. Subramanya, Bikash Mandal, John Hammond, S. W. Scott und R. W. Briddon. „Argemone mexicana (Mexican prickly poppy)“. In Encyclopedia of Plant Viruses and Viroids, 189. New Delhi: Springer India, 2019. http://dx.doi.org/10.1007/978-81-322-3912-3_81.
Der volle Inhalt der QuelleKonferenzberichte zum Thema "PopPK"
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Bitzer, M., L. Nguyen, S. Chapel, T. Meyer, AL Cheng, AB El-Khoueiry, RK Kelley und GK Abou-Alfa. „Integrierte populations-pharmakokinetische (PopPK) Analyse von Cabozantinib (C) bei Patienten (Pts) mit verschiedenen Krebsarten einschließlich fortgeschrittenem hepatozellulärem Karzinom (HCC)“. In Viszeralmedizin 2019. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1695301.
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Ferron-Brady, Geraldine, Chetan Rathi, Jon Collins, Herbert Struemper, Joanna Opalinska und Roxanne C. Jewell. „Abstract CT196: Therapeutic dose selection for belantamab mafodotin, a BCMA-targeting agent, in patients with relapsed/refractory multiple myeloma (RRMM): Application of population pharmacokinetics (PopPK) and exposure-response (E-R) analyses“. In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-ct196.
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Lapeyre, Matthieu, Steve N'Guyen, Alexandre Le Falher und Pierre-Yves Oudeyer. „Rapid morphological exploration with the Poppy humanoid platform“. In 2014 IEEE-RAS 14th International Conference on Humanoid Robots (Humanoids 2014). IEEE, 2014. http://dx.doi.org/10.1109/humanoids.2014.7041479.
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Wade, D., und The POPPI investigators. „Deeper Insights from the Provision of Psychological Support to People in Intensive Care (POPPI) Trial - the POPPI Trial Psychologist’s View“. In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a7296.
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Lapeyre, Matthieu, Pierre Rouanet und Pierre-Yves Oudeyer. „The poppy humanoid robot: Leg design for biped locomotion“. In 2013 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS 2013). IEEE, 2013. http://dx.doi.org/10.1109/iros.2013.6696375.
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Stefanski, Andrzej, Jerzy Wojewoda, Tomasz Kapitaniak und John Brindley. „Estimation of the Largest Lyapunov Exponent of Discontinuous Systems Using Chaos Synchronization“. In ASME 1999 Design Engineering Technical Conferences. American Society of Mechanical Engineers, 1999. http://dx.doi.org/10.1115/detc99/vib-8041.
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Abstract Properties of chaos synchronization have been used for estimation of the largest Lyapunov exponent of a discontinuous mechanical system. A method for such estimation is proposed and an example is shown, based on coupling of two identical systems with dry friction which is modelled according to the Popp-Stelter formula.
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Popov, Dmitry, Alexandr Klimchik und Ilya Afanasyev. „Design and Stiffness Analysis of 12 DoF Poppy-inspired Humanoid“. In 14th International Conference on Informatics in Control, Automation and Robotics. SCITEPRESS - Science and Technology Publications, 2017. http://dx.doi.org/10.5220/0006432000660078.
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Tai, Xiao Hui, Suraj R. Nair und Shikhar Mehra. „Poster - Mapping Opium Poppy Cultivation in Afghanistan Using Satellite Imagery“. In COMPASS '21: ACM SIGCAS Conference on Computing and Sustainable Societies. New York, NY, USA: ACM, 2021. http://dx.doi.org/10.1145/3460112.3472308.
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Lapeyre, Matthieu, Pierre Rouanet, Jonathan Grizou, Steve N'Guyen, Alexandre Le Falher, Fabien Depraetre und Pierre-Yves Oudeyer. „Poppy: Open source 3D printed robot for experiments in developmental robotics“. In 2014 Joint IEEE International Conferences on Development and Learning and Epigenetic Robotics (ICDL-Epirob). IEEE, 2014. http://dx.doi.org/10.1109/devlrn.2014.6982977.
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Nakazawa, Akihiro, Jong-Hwan Kim, Takuji Mitani, Shinya Odagawa, Tomomi Takeda, Chiaki Kobayashi und Osamu Kashimura. „A study on detecting the poppy field using hyperspectral remote sensing techniques“. In IGARSS 2012 - 2012 IEEE International Geoscience and Remote Sensing Symposium. IEEE, 2012. http://dx.doi.org/10.1109/igarss.2012.6352532.
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Kidwell, David. Options to Distinguish Heroin and Poppy Seed Use. Fort Belvoir, VA: Defense Technical Information Center, Juli 1989. http://dx.doi.org/10.21236/ada211496.
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Hayes, Ashton L. A Microgrant Supported Poppy Cultivation Renouncement Program for Afghanistan. Fort Belvoir, VA: Defense Technical Information Center, Februar 2009. http://dx.doi.org/10.21236/ada494726.
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