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Mi, Kun, Shanju Pu, Yixuan Hou, Lei Sun, Kaixiang Zhou, Wenjin Ma, Xiangyue Xu et al. „Optimization and Validation of Dosage Regimen for Ceftiofur against Pasteurella multocida in Swine by Physiological Based Pharmacokinetic–Pharmacodynamic Model“. International Journal of Molecular Sciences 23, Nr. 7 (28.03.2022): 3722. http://dx.doi.org/10.3390/ijms23073722.
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Model informed drug development is a valuable tool for drug development and clinical application due to its ability to integrate variability and uncertainty of data. This study aimed to determine an optimal dosage of ceftiofur against P. multocida by ex vivo pharmacokinetic/pharmacodynamic (PK/PD) model and validate the dosage regimens by Physiological based Pharmacokinetic-Pharmacodynamic (PBPK/PD) model. The pharmacokinetic profiles of ceftiofur both in plasma and bronchoalveolar lavage fluid (BALF) are determined. PD performance of ceftiofur against P. multocida was investigated. By establishing PK/PD model, PK/PD parameters and doses were determined. PBPK model and PBPK/PD model were developed to validate the dosage efficacy. The PK/PD parameters, AUC0–24 h/MIC, for bacteriostatic action, bactericidal action and elimination were determined as 44.02, 89.40, and 119.90 h and the corresponding dosages were determined as 0.22, 0.46, and 0.64 mg/kg, respectively. AUC24 h/MIC and AUC 72 h/MIC are simulated by PBPK model, compared with the PK/PD parameters, the therapeutic effect can reach probability of target attainment (PTA) of 90%. The time-courses of bacterial growth were predicted by the PBPK/PD model, which indicated the dosage of 0.46 mg/kg body weight could inhibit the bacterial growth and perform good bactericidal effect.
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Jeong, Yoo-Seong, Min-Soo Kim, Nora Lee, Areum Lee, Yoon-Jee Chae, Suk-Jae Chung und Kyeong-Ryoon Lee. „Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans“. Pharmaceutics 13, Nr. 6 (29.05.2021): 813. http://dx.doi.org/10.3390/pharmaceutics13060813.
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Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.
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Dallmann, A., P. Mian, P. Annaert, M. Pfister, K. Allegaert und J. van den Anker. „P21 PBPK modeling in pregnancy: achievements, shortcomings and future perspectives“. Archives of Disease in Childhood 104, Nr. 6 (17.05.2019): e25.2-e25. http://dx.doi.org/10.1136/archdischild-2019-esdppp.59.
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BackgroundPhysiologically-based pharmacokinetic (PBPK) models are considered a promising approach to better characterize and anticipate the effect of physiological changes on pharmacokinetics in pregnant women. Consequently, multiple pregnancy PBPK models have been developed and verified over the past years. Using acetaminophen (paracetamol) as example, PBPK modeling can provide specific insights into the expected pharmacokinetic changes throughout pregnancy.MethodsTo obtain an overview of pregnancy PBPK models, the scientific literature was systematically screened for publications with a focus on pharmaceutical applications using relevant keywords. Additionally, a pregnancy PBPK model for acetaminophen was developed with the Open Systems Pharmacology software suite (www.open-systems-pharmacology.org) following an established workflow. After model verification around gestational week 30, the model was scaled to earlier stages of pregnancy and molar dose fractions converted to acetaminophen metabolites were estimated for each trimester.ResultsOver the past years, more than 60 different pregnancy PBPK models for more than have 40 drugs been published. More than 70% of these models were developed for the third trimester, while few models have been applied to the first trimester. The developed PBPK model for acetaminophen indicated that the median dose fraction of acetaminophen converted to the reactive metabolite N-acetyl-p-benzoquinonimine (NAPQI) was 11%, 9.0% and 8.2% in the first, second and third trimester, respectively, while for non-pregnant women a value of 7.7% was simulated.ConclusionWhile the overall availability and quality of pregnancy PBPK models is varying considerably, the efforts to establish such models are promising in that they reflect an increased awareness of the necessity to better characterize pharmacokinetics during pregnancy. This is illustrated by the developed PBPK model for acetaminophen where information on NAPQI-formation in vivo is hitherto lacking. Although PBPK models are not a substitute for clinical trials, they constitute an important tool for clinicians in case of missing or incomplete information.Disclosure(s)Nothing to disclose
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Nauwelaerts, Nina, Julia Macente, Neel Deferm, Rodolfo Hernandes Bonan, Miao-Chan Huang, Martje Van Neste, David Bibi et al. „Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling—A Contribution from the ConcePTION Project“. Pharmaceutics 15, Nr. 5 (11.05.2023): 1469. http://dx.doi.org/10.3390/pharmaceutics15051469.
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Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten physiochemically diverse medicines. First, PBPK models were developed for “non-lactating” adult individuals in PK-Sim/MoBi v9.1 (Open Systems Pharmacology). The PBPK models predicted the area-under-the-curve (AUC) and maximum concentrations (Cmax) in plasma within a two-fold error. Next, the PBPK models were extended to include lactation physiology. Plasma and human milk concentrations were simulated for a three-months postpartum population, and the corresponding AUC-based milk-to-plasma (M/P) ratios and relative infant doses were calculated. The lactation PBPK models resulted in reasonable predictions for eight medicines, while an overprediction of human milk concentrations and M/P ratios (>2-fold) was observed for two medicines. From a safety perspective, none of the models resulted in underpredictions of observed human milk concentrations. The present effort resulted in a generic workflow to predict medicine concentrations in human milk. This generic PBPK model represents an important step towards an evidence-based safety assessment of maternal medication during lactation, applicable in an early drug development stage.
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Kovar, Lukas, Christina Schräpel, Dominik Selzer, Yvonne Kohl, Robert Bals, Matthias Schwab und Thorsten Lehr. „Physiologically-Based Pharmacokinetic (PBPK) Modeling of Buprenorphine in Adults, Children and Preterm Neonates“. Pharmaceutics 12, Nr. 6 (23.06.2020): 578. http://dx.doi.org/10.3390/pharmaceutics12060578.
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Buprenorphine plays a crucial role in the therapeutic management of pain in adults, adolescents and pediatric subpopulations. However, only few pharmacokinetic studies of buprenorphine in children, particularly neonates, are available as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling allows the prediction of drug exposure in pediatrics based on age-related physiological differences. The aim of this study was to predict the pharmacokinetics of buprenorphine in pediatrics with PBPK modeling. Moreover, the drug-drug interaction (DDI) potential of buprenorphine with CYP3A4 and P-glycoprotein perpetrator drugs should be elucidated. A PBPK model of buprenorphine and norbuprenorphine in adults has been developed and scaled to children and preterm neonates, accounting for age-related changes. One-hundred-percent of the predicted AUClast values in adults (geometric mean fold error (GMFE): 1.22), 90% of individual AUClast predictions in children (GMFE: 1.54) and 75% in preterm neonates (GMFE: 1.57) met the 2-fold acceptance criterion. Moreover, the adult model was used to simulate DDI scenarios with clarithromycin, itraconazole and rifampicin. We demonstrate the applicability of scaling adult PBPK models to pediatrics for the prediction of individual plasma profiles. The novel PBPK models could be helpful to further investigate buprenorphine pharmacokinetics in various populations, particularly pediatric subgroups.
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Pilla Reddy, Venkatesh, Adrian J. Fretland, Diansong Zhou, Shringi Sharma, Buyun Chen, Karthick Vishwanathan, Dermot F. McGinnity, Yan Xu und Joseph A. Ware. „Mechanistic physiology-based pharmacokinetic modeling to elucidate vincristine-induced peripheral neuropathy following treatment with novel kinase inhibitors“. Cancer Chemotherapy and Pharmacology 88, Nr. 3 (02.06.2021): 451–64. http://dx.doi.org/10.1007/s00280-021-04302-5.
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Abstract Purpose Limited information is available regarding the drug–drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. Methods A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. Results While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration–time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. Conclusion Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.
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Yang, Yiting, Ping Li, Zexin Zhang, Zhongjian Wang, Li Liu und Xiaodong Liu. „Prediction of Cyclosporin-Mediated Drug Interaction Using Physiologically Based Pharmacokinetic Model Characterizing Interplay of Drug Transporters and Enzymes“. International Journal of Molecular Sciences 21, Nr. 19 (24.09.2020): 7023. http://dx.doi.org/10.3390/ijms21197023.
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Uptake transporter organic anion transporting polypeptides (OATPs), efflux transporters (P-gp, BCRP and MRP2) and cytochrome P450 enzymes (CYP450s) are widely expressed in the liver, intestine or kidney. They coordinately work to control drug disposition, termed as “interplay of transporters and enzymes”. Cyclosporine A (CsA) is an inhibitor of OATPs, P-gp, MRP2, BCRP and CYP3As. Drug–drug interaction (DDI) of CsA with victim drugs occurs via disordering interplay of transporters and enzymes. We aimed to establish a whole-body physiologically-based pharmacokinetic (PBPK) model which predicts disposition of CsA and nine victim drugs including atorvastatin, cerivastatin, pravastatin, rosuvastatin, fluvastatin, simvastatin, lovastatin, repaglinide and bosentan, as well as drug–drug interactions (DDIs) of CsA with nine victim drugs to investigate the integrated effect of enzymes and transporters in liver, intestinal and kidney on drug disposition. Predictions were compared with observations. Most of the predictions were within 0.5–2.0 folds of observations. Atorvastatin was represented to investigate individual contributions of transporters and CYP3As to atorvastatin disposition and their integrated effect. The contributions to atorvastatin disposition were hepatic OATPs >> hepatic CYP3A > intestinal CYP3As ≈ efflux transporters (P-gp/BCRP/MRP2). The results got the conclusion that the developed PBPK model characterizing the interplay of enzymes and transporters was successfully applied to predict the pharmacokinetics of 10 OATP substrates and DDIs of CsA with 9 victim drugs.
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Wills, Kenneth H., Stephen J. Behan, Michael J. Nance, Jessica L. Dawson, Thomas M. Polasek, Ashley M. Hopkins, Madelé van Dyk und Andrew Rowland. „Combining Therapeutic Drug Monitoring and Pharmacokinetic Modelling Deconvolutes Physiological and Environmental Sources of Variability in Clozapine Exposure“. Pharmaceutics 14, Nr. 1 (27.12.2021): 47. http://dx.doi.org/10.3390/pharmaceutics14010047.
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Background: Clozapine is a key antipsychotic drug for treatment-resistant schizophrenia but exhibits highly variable pharmacokinetics and a propensity for serious adverse effects. Currently, these challenges are addressed using therapeutic drug monitoring (TDM). This study primarily sought to (i) verify the importance of covariates identified in a prior clozapine population pharmacokinetic (popPK) model in the absence of environmental covariates using physiologically based pharmacokinetic (PBPK) modelling, and then to (ii) evaluate the performance of the popPK model as an adjunct or alternative to TDM-guided dosing in an active TDM population. Methods: A popPK model incorporating age, metabolic activity, sex, smoking status and weight was applied to predict clozapine trough concentrations (Cmin) in a PBPK-simulated population and an active TDM population comprising 142 patients dosed to steady state at Flinders Medical Centre in Adelaide, South Australia. Post hoc analyses were performed to deconvolute the impact of physiological and environmental covariates in the TDM population. Results: Analysis of PBPK simulations confirmed age, cytochrome P450 1A2 activity, sex and weight as physiological covariates associated with variability in clozapine Cmin (R2 = 0.7698; p = 0.0002). Prediction of clozapine Cmin using a popPK model based on these covariates accounted for <5% of inter-individual variability in the TDM population. Post hoc analyses confirmed that environmental covariates accounted for a greater proportion of the variability in clozapine Cmin in the TDM population. Conclusions: Variability in clozapine exposure was primarily driven by environmental covariates in an active TDM population. Pharmacokinetic modelling can be used as an adjunct to TDM to deconvolute sources of variability in clozapine exposure.
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Kim, Min-Soo, Nora Lee, Areum Lee, Yoon-Jee Chae, Suk-Jae Chung und Kyeong-Ryoon Lee. „Model-Based Prediction of Acid Suppression and Proposal of a New Dosing Regimen of Fexuprazan in Humans“. Pharmaceuticals 15, Nr. 6 (03.06.2022): 709. http://dx.doi.org/10.3390/ph15060709.
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Fexuprazan is a potassium-competitive acid blocker (P-CAB). The compounds in this newly developed drug family suppress intragastric acidity. As there are already other acid-suppressing drugs on the market, such as H2 antagonists and proton pump inhibitors (PPIs), it would be informative to compare the biological effects of fexuprazan against another approved drug with the same indication. The drug concentration predicted by the pharmacokinetic (PK) model could serve as an input function for a pharmacodynamic (PD) model. The apparent pharmacokinetics of fexuprazan could be described by a simpler model. However, a physiologically based pharmacokinetic (PBPK) model was developed in a previous study. A one-compartment model was also proposed in the present study. Both the newly suggested model and the previously validated PBPK model were used as input functions of the PD models. Our simulation revealed that the effects of fexuprazan could be effectively simulated by the proposed PK–PD models. A PK–PD model was also proposed for the oral administration of the PPI reference drug esomeprazole. A model-based analysis was then performed for intragastric pH using several dosing methods. The expected pH could be predicted for both drugs under several dosing regimens using the proposed PK–PD models.
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Bachelet, Delphine, Marc-André Verner, Monica Neri, Émilie Cordina Duverger, Corinne Charlier, Patrick Arveux, Sami Haddad und Pascal Guénel. „Breast Cancer and Exposure to Organochlorines in the CECILE Study: Associations with Plasma Levels Measured at the Time of Diagnosis and Estimated during Adolescence“. International Journal of Environmental Research and Public Health 16, Nr. 2 (18.01.2019): 271. http://dx.doi.org/10.3390/ijerph16020271.
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Exposure to environmental chemicals with hormonal effects, such as organochlorine compounds (OCs), during developmental periods of breast cells may have an impact on the incidence of breast cancer later in life. However, the assessment of exposure to these chemicals that occurred in early life at the time of breast cancer development in adult women is a difficult challenge in epidemiological studies. Plasma levels of the OCs p,p’-dichlorodiphenyl dichloroethene (DDE) and polychlorinated biphenyl congener 153 (PCB153) were measured in 695 cases and 1055 controls of a population-based case-control study conducted in France (CECILE study). Based on these values, we used a physiologically-based pharmacokinetic (PBPK) model to estimate PCB153 levels at age 11–20 years when the women were adolescents. Overall, there was no clear association between breast cancer risk and measured levels of DDE and PCB153 at the time of diagnosis, but there was a trend of decreasing odds ratios of breast cancer with increasing DDE and PCB153 levels in women aged 50 years and over. The PBPK model revealed that PCB153 concentrations estimated during adolescence were highest in the youngest women born after 1960 who reached adolescence at a time when environmental contamination was maximum, and very low in the oldest women who attained adolescence before the contamination peak. Negative associations between breast cancer and PCB153 estimates during adolescence were also found. The negative associations between DDE and PCB153 levels measured at the time of diagnosis or estimated during adolescence in our study were unexplained. Further investigations are needed to clarify whether this finding is real or related to study artifacts. However, this study suggests that using PBPK models in epidemiological studies to back-estimate OC exposures during early life stages may be useful to address critical questions on cancer development.
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Berghausen, Joerg, Frank Hans Seiler, Nathalie Gobeau und Bernard Faller. „Simulated rat intestinal fluid improves oral exposure prediction for poorly soluble compounds over a wide dose range“. ADMET & DMPK 4, Nr. 1 (30.03.2016): 35. http://dx.doi.org/10.5599/admet.4.1.258.
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<p class="ADMETabstracttext">Solubility can be the absorption limiting factor for drug candidates and is therefore a very important input parameter for oral exposure prediction of compounds with limited solubility. Biorelevant media of the fasted and fed state have been published for humans, as well as for dogs in the fasted state. In a drug discovery environment, rodents are the most common animal model to assess the oral exposure of drug candidates. In this study a rat simulated intestinal fluid (rSIF) is proposed as a more physiologically relevant media to describe drug solubility in rats. Equilibrium solubility in this medium was tested as input parameter for physiologically-based pharmacokinetics (PBPK) simulations of oral pharmacokinetics in the rat. Simulations were compared to those obtained using other solubility values as input parameters, like buffer at pH 6.8, human simulated intestinal fluid and a comprehensive dissolution assay based on rSIF. Our study on nine different compounds demonstrates that the incorporation of rSIF equilibrium solubility values into PBPK models of oral drug exposure can significantly improve the reliability of simulations in rats for doses up to 300 mg/kg compared to other media. The comprehensive dissolution assay may help to improve further simulation outcome, but the greater experimental effort as compared to equilibrium solubility may limit its use in a drug discovery environment. Overall, PBPK simulations based on solubility in the proposed rSIF medium can improve prioritizing compounds in drug discovery as well as planning dose escalation studies, e.g. during toxicological investigations.</p>
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Liu, Rongrui, Tim R. Zacharewski, Rory B. Conolly und Qiang Zhang. „A Physiologically Based Pharmacokinetic (PBPK) Modeling Framework for Mixtures of Dioxin-like Compounds“. Toxics 10, Nr. 11 (17.11.2022): 700. http://dx.doi.org/10.3390/toxics10110700.
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Humans are exposed to persistent organic pollutants, such as dioxin-like compounds (DLCs), as mixtures. Understanding and predicting the toxicokinetics and thus internal burden of major constituents of a DLC mixture is important for assessing their contributions to health risks. PBPK models, including dioxin models, traditionally focus on one or a small number of compounds; developing new or extending existing models for mixtures often requires tedious, error-prone coding work. This lack of efficiency to scale up for multi-compound exposures is a major technical barrier toward large-scale mixture PBPK simulations. Congeners in the DLC family, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), share similar albeit quantitatively different toxicokinetic and toxicodynamic properties. Taking advantage of these similarities, here we reported the development of a human PBPK modeling framework for DLC mixtures that can flexibly accommodate an arbitrary number of congeners. Adapted from existing TCDD models, our mixture model contains the blood and three diffusion-limited compartments—liver, fat, and rest of the body. Depending on the number of congeners in a mixture, varying-length vectors of ordinary differential equations (ODEs) are automatically generated to track the tissue concentrations of the congeners. Shared ODEs are used to account for common variables, including the aryl hydrocarbon receptor (AHR) and CYP1A2, to which the congeners compete for binding. Binary and multi-congener mixture simulations showed that the AHR-mediated cross-induction of CYP1A2 accelerates the sequestration and metabolism of DLC congeners, resulting in consistently lower tissue burdens than in single exposure, except for the liver. Using dietary intake data to simulate lifetime exposures to DLC mixtures, the model demonstrated that the relative contributions of individual congeners to blood or tissue toxic equivalency (TEQ) values are markedly different than those to intake TEQ. In summary, we developed a mixture PBPK modeling framework for DLCs that may be utilized upon further improvement as a quantitative tool to estimate tissue dosimetry and health risks of DLC mixtures.
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Ciffroy, Philippe, T. Tanaka, E. Johansson und C. Brochot. „Linking fate model in freshwater and PBPK model to assess human internal dosimetry of B(a)P associated with drinking water“. Environmental Geochemistry and Health 33, Nr. 4 (02.04.2011): 371–87. http://dx.doi.org/10.1007/s10653-011-9382-6.
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Gaohua, Lu, Khaled Abduljalil, Masoud Jamei, Trevor N. Johnson und Amin Rostami-Hodjegan. „A pregnancy physiologically based pharmacokinetic (p-PBPK) model for disposition of drugs metabolized by CYP1A2, CYP2D6 and CYP3A4“. British Journal of Clinical Pharmacology 74, Nr. 5 (09.10.2012): 873–85. http://dx.doi.org/10.1111/j.1365-2125.2012.04363.x.
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Templeton, Ian E., Terry Podoll, Cecile Marie Krejsa und J. Greg Slatter. „A Mechanistic Physiologically Based Pharmacokinetic (PBPK) Drug Interaction Model for the Mouse Double Minute 2 (MDM2) Inhibitor KRT-232“. Blood 136, Supplement 1 (05.11.2020): 9–10. http://dx.doi.org/10.1182/blood-2020-135987.
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Background: KRT-232 is a potent, selective, orally available, targeted inhibitor of human MDM2 homolog interactions with tumor suppressor protein 53 (p53). KRT-232 is under development for treatment of myeloproliferative neoplasms, acute myeloid leukemia and Merkel cell carcinoma. KRT-232 is a highly permeable 568.6 g/mol, monoprotic carboxylic acid (pKa 4.35); elimination involves primarily biliary-fecal excretion of an acyl glucuronide metabolite (M1) and enteric glucuronide hydrolysis with enterohepatic recirculation of parent drug. M1 is a 744.7 g/mol monoprotic acid with pKa 3.32 and 1/5th the MDM2 inhibitory potency of KRT-232. Plasma protein binding (fup) of KRT-232 and M1 were ~0.026 and ~0.006, respectively. Static model drug-drug interaction (DDI) calculations (FDA-CDER. 2020) indicated a potential minor DDI with substrates of cytochrome P450s (CYP) CYP3A4 and CYP2C8, UGT1A1, P-glycoprotein 1 (P-gp) and OATP1B1/3. Here, a 'fit-for-purpose' PBPK model for KRT-232 was developed using physicochemical, preclinical (in vitroandin vivo) and clinical pharmacokinetic (PK) data (KartosData on file; Ye et al.Xenobiotica. 2015; Gluck et al.Invest New Drugs. 2020 [Study A]). Methods:Simcyp Simulator V17 (release 1; 27/11/2017; 17.0.90.0) was used. In vitro kinetic parameters: In vitroKi for competitive inhibition of CYP2C8 was 3.8 and 0.17 µM for KRT-232 and M1, respectively.In vitroKI and kinact for mechanism-based inhibition of CYP3A4 by KRT-232 were 28 µM and 4.14 h-1, respectively. Estimatedin vitroKi values for KRT-232-mediated inhibition of UGT1A1, P-gp, OATP1B1 and OATP1B3, were 1.9, 14.8, 4.9 and 6.9 µM. For M1-mediated inhibition of UGT1A1, OATP1B1 and OATP1B3, values were 2.3, 0.393 and 0.606 µM. Model development and verification:KRT-232 absorption was described by a first-order process; fraction absorbed was assumed to be 100% and the absorption rate constant was manually optimized using observed mean plasma concentration data from Part 1 of Study A. KRT-232 clearance was based onin vitroformation clearance of M1 in human liver microsomes, scaled up 4-fold based on observed oral clearance of KRT-232 (Wood et al.Drug Metab Dispos. 2017). KRT-232 distribution volume was described by a minimal PBPK model. KRT-232 and M1 DDI parameters were based onin vitrodata. M1 clearance was manually optimized using mean observed data from Study A (Part 1, 240 mg dose), and distribution volume was predicted by the Simulator using Method 1 and a full PBPK model. PBPK simulated data were compared with patient PK data collected during Part 2 of Study A. Model application:The model predicted potential DDI after steady state (SS) 240 mg once daily KRT-232 administration with substrates of CYP3A4, CYP2C8, UGT1A1, P-gp and OATP1B1/3. DDI simulations included 100 virtual subjects assigned to 10 virtual trials (N=10 each). Population estimates of geometric mean and median Cmax and AUC0-∞ ratios were generated. A "worst case" sensitivity analysis was performed by using a 10-fold increase inin vitroCYP3A4 interaction potency (KI, EC50) relative to the measuredin vitrovalue. Results:Figure 1shows simulated SS mean and individual observed KRT-232 and M1 concentration data from Part 2 of Study A. SS KRT-232 Cmax, AUC0-24h and t1/2 were predicted within 0.80-1.25-fold of observed PK data and tmax was under-predicted (0.36-fold) by the model (Table 1). M1 Cmax and AUC0-24h were within 0.80-1.25-fold of observed PK data on Day 1 (not shown). M1 Cmax on Day 7 was within 0.80-1.25-fold of observed PK data and SS AUC0-24h, t1/2, and tmax were underpredicted (0.72, 0.79 and 0.61-fold) relative to observed PK data. In all simulated DDIs, no clinically significant interaction was predicted for SS 240 mg doses of KRT-232 since predicted Cmax and AUC0-∞ geometric mean ratio (GMR) changes were less than 1.25-fold (Table 2). The CYP3A4 DDI simulation gave a population GMR (90% CI) for Cmax and AUC0-∞ of 1.07 (1.06, 1.09) and 1.15 (1.12, 1.17), respectively. In a sensitivity check, predicted midazolam Cmax and AUC0-∞ after a 10-fold reduction ofin vitroKI and EC50 were 1.44-fold and 2.18-fold, respectively. Although unlikely, a weak CYP3A4 DDI could not be definitively excluded. Conclusions: Mean plasma exposure of KRT-232 and M1 and inter-individual variability were adequately described by the PBPK model. No clinically significant DDI were predicted based on Cmax and AUC0-∞ GMR changes of less than 1.25-fold. Disclosures Templeton: Certara UK, LTD.:Current Employment.Podoll:IV/PO, LLC:Consultancy.Krejsa:Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company;Seattle Genetics:Current equity holder in publicly-traded company;Acerta Pharma:Current equity holder in private company.Slatter:Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company;Amgen:Divested equity in a private or publicly-traded company in the past 24 months.
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Smith, Jordan N., Kari A. Gaither und Paritosh Pande. „Competitive Metabolism of Polycyclic Aromatic Hydrocarbons (PAHs): An Assessment Using In Vitro Metabolism and Physiologically Based Pharmacokinetic (PBPK) Modeling“. International Journal of Environmental Research and Public Health 19, Nr. 14 (06.07.2022): 8266. http://dx.doi.org/10.3390/ijerph19148266.
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Humans are routinely exposed to complex mixtures such as polycyclic aromatic hydrocarbons (PAHs) rather than to single compounds, as are often assessed for hazards. Cytochrome P450 enzymes (CYPs) metabolize PAHs, and multiple PAHs found in mixtures can compete as substrates for individual CYPs (e.g., CYP1A1, CYP1B1, etc.). The objective of this study was to assess competitive inhibition of metabolism of PAH mixtures in humans and evaluate a key assumption of the Relative Potency Factor approach that common human exposures will not cause interactions among mixture components. To test this objective, we co-incubated binary mixtures of benzo[a]pyrene (BaP) and dibenzo[def,p]chrysene (DBC) in human hepatic microsomes and measured rates of enzymatic BaP and DBC disappearance. We observed competitive inhibition of BaP and DBC metabolism and measured inhibition coefficients (Ki), observing that BaP inhibited DBC metabolism more potently than DBC inhibited BaP metabolism (0.061 vs. 0.44 µM Ki, respectively). We developed a physiologically based pharmacokinetic (PBPK) interaction model by integrating PBPK models of DBC and BaP and incorporating measured metabolism inhibition coefficients. The PBPK model predicts significant increases in BaP and DBC concentrations in blood AUCs following high oral doses of PAHs (≥100 mg), five orders of magnitude higher than typical human exposures. We also measured inhibition coefficients of Supermix-10, a mixture of the most abundant PAHs measured at the Portland Harbor Superfund Site, on BaP and DBC metabolism. We observed similar potencies of inhibition coefficients of Supermix-10 compared to BaP and DBC. Overall, results of this study demonstrate that these PAHs compete for the same enzymes and, at high doses, inhibit metabolism and alter internal dosimetry of exposed PAHs. This approach predicts that BaP and DBC exposures required to observe metabolic interaction are much higher than typical human exposures, consistent with assumptions used when applying the Relative Potency Factor approach for PAH mixture risk assessment.
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Russo, Francesca M., Felix De Bie, Ryan Hodges, Alan Flake und Jan Deprest. „Sildenafil for Antenatal Treatment of Congenital Diaphragmatic Hernia: From Bench to Bedside“. Current Pharmaceutical Design 25, Nr. 5 (03.06.2019): 601–8. http://dx.doi.org/10.2174/1381612825666190320151856.
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Background: Persistent pulmonary hypertension (PPH) is one of the main causes of mortality and morbidity in infants affected by congenital diaphragmatic hernia (CDH). Since the structural changes that lead to PPH take place already in utero, a treatment starting in the prenatal phase may prevent the occurrence of this complication. Objective: To summarize the development process of antenatal sildenafil for CDH. Methods: The pharmacokinetics and efficacy of sildenafil have been assessed in the rat and the rabbit model. The transfer of the drug through the human placenta has been measured with the ex-vivo placenta perfusion model. Results from this experiment are being incorporated in a pregnancy-physiologically based pharmacokinetic (p- PBPK) model. A phase I-IIb placental transfer and safety study is ongoing. Results: Sildenafil administration to pregnant rats and rabbits led to therapeutic foetal drug levels without maternal and foetal toxicity, although it was associated with impaired vascular development in foetuses with nonhypoplastic lungs. Peak concentrations and 24-hour exposure were higher in pregnant rabbits compared to nonpregnant ones. In rat and rabbit foetuses with CDH, sildenafil rescued the lung vascular anomalies and partially improved parenchymal development. Sildenafil crossed the human placenta at a high rate ex-vivo, independently from the initial maternal concentration. Conclusion: There is preclinical evidence that maternally administered sildenafil prevents the vascular changes that lead to PPH in CDH newborns. The phase I/IIb clinical study together with the p-PBPK model will define the maternal dose needed for a therapeutic effect in the foetus. Foetal safety will be investigated both in the clinical study and in the sheep. The final step will be a multicentre, randomized, placebo-controlled trial.
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Kato, Takafumi, Tsuyoshi Mikkaichi, Yasushi Yoshigae, Noriko Okudaira, Takako Shimizu, Takashi Izumi, Shuichi Ando und Yoshiaki Matsumoto. „Quantitative analysis of an impact of P-glycoprotein on edoxaban's disposition using a human physiologically based pharmacokinetic (PBPK) model“. International Journal of Pharmaceutics 597 (März 2021): 120349. http://dx.doi.org/10.1016/j.ijpharm.2021.120349.
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Verscheijden, Laurens F. M., Jan B. Koenderink, Saskia N. de Wildt und Frans G. M. Russel. „Differences in P-glycoprotein activity in human and rodent blood–brain barrier assessed by mechanistic modelling“. Archives of Toxicology 95, Nr. 9 (15.07.2021): 3015–29. http://dx.doi.org/10.1007/s00204-021-03115-y.
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AbstractVariation in the efficacy and safety of central nervous system drugs between humans and rodents can be explained by physiological differences between species. An important factor could be P-glycoprotein (Pgp) activity in the blood–brain barrier (BBB), as BBB expression of this drug efflux transporter is reportedly lower in humans compared to mouse and rat and subject to an age-dependent increase. This might complicate animal to human extrapolation of brain drug disposition and toxicity, especially in children. In this study, the potential species-specific effect of BBB Pgp activity on brain drug exposure was investigated. An age-dependent brain PBPK model was used to predict cerebrospinal fluid and brain mass concentrations of Pgp substrate drugs. For digoxin, verapamil and quinidine, in vitro kinetic data on their transport by Pgp were derived from literature and used to scale to in vivo parameters. In addition, age-specific digoxin transport was simulated for children with a postnatal age between 25 and 81 days. BBB Pgp activity in the model was optimized using measured CSF data for the Pgp substrates ivermectin, indinavir, vincristine, docetaxel, paclitaxel, olanzapine and citalopram, as no useful in vitro data were available. Inclusion of Pgp activity in the model resulted in optimized predictions of their brain concentration. Total brain-to-plasma AUC values (Kp,brain) in the simulations without Pgp were divided by the Kp,brain values with Pgp. Kp ratios ranged from 1 to 45 for the substrates investigated. Comparison of human with rodent Kp,brain ratios indicated ≥ twofold lower values in human for digoxin, verapamil, indinavir, paclitaxel and citalopram and ≥ twofold higher values for vincristine. In conclusion, BBB Pgp activity appears species-specific. An age-dependent PBPK model-based approach could be useful to extrapolate animal data to human adult and paediatric predictions by taking into account species-specific and developmental BBB Pgp expression.
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Nguyen, Dung N., Xiusheng Miao, Mindy Magee, Guoying Tai, Peter D. Gorycki und Katy P. Moore. „1315. No Dose Adjustment of Metformin with Fostemsavir Coadministration Based on Mechanistic Static and Physiologically Based Pharmacokinetic Models“. Open Forum Infectious Diseases 7, Supplement_1 (01.10.2020): S669. http://dx.doi.org/10.1093/ofid/ofaa439.1497.
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Abstract Background Fostemsavir (FTR) is an oral prodrug of the first-in-class attachment inhibitor temsavir (TMR) which is being evaluated in patients with multidrug resistant HIV-1 infection. In vitro studies indicated that TMR and its 2 major metabolites are inhibitors of organic cation transporters (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs). To assess the clinical relevance, of OCT and MATE inhibition, mechanistic static DDI prediction with calculated Imax,u/IC50 ratios was below the cut-off limits for a DDI flag based on FDA guidelines and above the cut-off limits for MATEs based on EMA guidelines. Methods Metformin is a commonly used probe substrate for OCT1, OCT2 and MATEs. To predict the potential for a drug interaction between TMR and metformin, a physiologically based pharmacokinetic (PBPK) model for TMR was developed based on its physicochemical properties, in vitro and in vivo data. The model was verified and validated through comparison with clinical data. The TMR PBPK model accurately described AUC and Cmax within 30% of the observed data for single and repeat dose studies with or without food. The SimCYP models for metformin and ritonavir were qualified using literature data before applications of DDI prediction for TMR Results TMR was simulated at steady state concentrations after repeated oral doses of FTR 600 mg twice daily which allowed assessment of the potential OCT1, OCT2, and MATEs inhibition by TMR and metabolites. No significant increase in metformin systemic exposure (AUC or Cmax) was predicted with FTR co-administration. In addition, a sensitivity analysis was conducted for either hepatic OCT1 Ki, or renal OCT2 and MATEs Ki values. The model output indicated that, a 10-fold more potent Ki value for TMR would be required to have a ~15% increase in metformin exposure Conclusion Based on mechanistic static models and PBPK modeling and simulation, the OCT1/2 and MATEs inhibition potential of TMR and its metabolites on metformin pharmacokinetics is not clinically significant. No dose adjustment of metformin is necessary when co-administered with FTR Disclosures Xiusheng Miao, PhD, GlaxoSmithKline (Employee) Mindy Magee, Doctor of Pharmacy, GlaxoSmithKline (Employee, Shareholder) Peter D. Gorycki, BEChe, MSc, PhD, GSK (Employee, Shareholder) Katy P. Moore, PharmD, RPh, ViiV Healthcare (Employee)
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Liu, Jian, Swan Lin, Anthony Huynh und Weiwei Tan. „Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib“. Pharmaceutics 16, Nr. 1 (17.01.2024): 118. http://dx.doi.org/10.3390/pharmaceutics16010118.
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Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) and EGFR-activating mutations. Proton-pump inhibitors decreased dacomitinib exposure. This analysis summarizes the effect of Histamine-2 receptor antagonists (H2RAs) on dacomitinib exposure. A within-patient comparison of the steady-state trough concentrations (Ctrough,ss) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RAs was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption physiologically based pharmacokinetic (PBPK) model was constructed and verified using clinical pharmacokinetic (PK) data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib’s PKs. The adjusted geometric mean of the dacomitinib Ctrough,ss of the dacomitinib parent, metabolite and active moiety following co-administration with an H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without an H2RA (p > 0.05). The PBPK modeling showed negligible change in dacomitinib maximum concentration (Cmax) and area under the drug concentration–time curve (AUC) over 0–24 h after H2RA administration when compared with those administered dacomitinib alone. Co-administration of an H2RA with dacomitinib is not expected to have any clinically relevant effect on dacomitinib exposure.
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Desai, Amit, Laura Kovanda, Christopher Lademacher, William Hope, Michael Neely, Peter Bonate und Andrea Edginton. „1396. Predictions of Isavuconazonium Sulfate Dosage in Patients Aged 6 Months: <18 Years by Physiologically Based Pharmacokinetic Modeling“. Open Forum Infectious Diseases 5, suppl_1 (November 2018): S429—S430. http://dx.doi.org/10.1093/ofid/ofy210.1227.
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Abstract Background Best practice to establish dosage regimens for “first-in-pediatric” clinical trials requires knowledge of efficacious and safe exposures in adults. Methods Pediatric equivalent doses were predicted for patients aged 6 months and <18 years using physiologically based pharmacokinetic (PBPK) modeling, and compared with predictions by allometric scaling. All simulations were completed using PK-Sim®, which implements a whole-body PBPK model with 15 organs and appropriate maturation of anatomical and physiological parameters for children. The adult PBPK model was built using knowledge of drug physico-chemistry and clearance partitioning (CYP3A4, CYP3A5, glomerular filtration). PK data following IV (40, 80, 160 mg 60-minute infusion) and oral (100, 200, 400 mg capsule) doses in adults were used for initial model development. This model was validated by matching observed adult concentrations after multiple oral 200 mg doses. From this adult model, a virtual pediatric population (n = 4,600) from 6 months to <18 years was created. Simulations with the pediatric model assessed optimal doses of isavuconazonium sulfate based on age and weight to achieve at least a median steady-state daily area under the curve (AUCss) of 100 mg hour/L, and the majority below 230 mg hour/L. These targets were derived from efficacy and safety data in clinical trials with adults. Results As shown in the figure, an isavuconazonium sulfate dose of 10 mg/kg is expected to result in AUCss within the target range for the majority of patients >1 year old, in agreement with that predicted by allometry for patients aged 2–17 years. For patients aged 6 months to 1 year, a dose of 6 mg/kg predicts comparable exposures. Conclusion A proposed isavuconazonium sulfate dose of 10 mg/kg administered every 8 hours for the first 2 days and once daily thereafter is predicted to result in safe and efficacious steady state exposures in patients aged 1–17 years, similar to predictions from allometric scaling for patients aged 2–17 years. For subjects aged 6 months to 1 year, a dose of 6 mg/kg is predicted to achieve similar exposures. These doses should be tested in clinical trials to confirm. Disclosures A. Desai, Astellas Pharma, Inc.: Employee, Salary. L. Kovanda, Astellas Pharma, Inc.: Employee, Salary. C. Lademacher, Astellas Pharma, Inc.: Employee, Salary. W. Hope, F2G: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Astellas: Grant Investigator and Investigator, Grant recipient and Research grant. Pfizer: Grant Investigator, Research support. Gilead: Consultant and Scientific Advisor, Consulting fee. P. Bonate, Astellas Pharma, Inc.: Employee, Salary. A. Edginton, Astellas Pharma Global Development, Inc.: Independent Contractor, Consulting fee.
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Zhou, Kaixiang, Meixia Huo, Wenjin Ma, Kun Mi, Xiangyue Xu, Samah Attia Algharib, Shuyu Xie und Lingli Huang. „Application of a Physiologically Based Pharmacokinetic Model to Develop a Veterinary Amorphous Enrofloxacin Solid Dispersion“. Pharmaceutics 13, Nr. 5 (22.04.2021): 602. http://dx.doi.org/10.3390/pharmaceutics13050602.
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Zoonotic intestinal pathogens threaten human health and cause huge economic losses in farming. Enrofloxacin (ENR) shows high antibacterial activity against common intestinal bacteria. However, its poor palatability and low aqueous solubility limit the clinical application of ENR. To obtain an ENR oral preparation with good palatability and high solubility, a granule containing an amorphous ENR solid dispersion (ENR-SD) was prepared. Meanwhile, a PBPK model of ENR in pigs was built based on the physiological parameters of pigs and the chemical-specific parameters of ENR to simulate the pharmacokinetics (PK) of ENR-SD granules in the intestinal contents. According to the results of parameter sensitivity analysis (PSA) and the predicted PK parameters at different doses of the model, formulation strategies and potential dose regimens against common intestinal infections were provided. The DSC and XRD results showed that no specific interactions existed between the excipients and ENR during the compatibility tests, and ENR presented as an amorphous form in ENR-SD. Based on the similar PK performance of ENR-SD granules and the commercial ENR soluble powder suggesting continued enhancement of the solubility of ENR, a higher drug concentration in intestinal contents could not be obtained. Therefore, a 1:5 ratio of ENR and stearic acid possessing a saturated aqueous solubility of 1190 ± 7.71 µg/mL was selected. The predictive AUC24h/MIC90 ratios against Campylobacter jejuni, Salmonella, and Escherichia coli were 133, 266 and 8520 (>100), respectively, suggesting that satisfactory efficacy against common intestinal infections would be achieved at a dose of 10 mg/kg b.w. once daily. The PSA results indicated that the intestinal absorption rate constant (Ka) was negatively correlated with the Cmax of ENR in the intestine, suggesting that we could obtain higher intestinal Cmax using P-gp inducers to reduce Ka, thus obtaining a higher Cmax. Our studies suggested that the PBPK model is an excellent tool for formulation and dose design.
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Mian, P., K. Allegaert, S. Conings, P. Annaert, D. Tibboel, M. Pfister, K. van Calsteren, JN van den Anker und A. Dallmann. „P66 Characterization of the pharmacokinetics of acetaminophen and its metabolites in the fetus through integration of placental transfer in a physiologically based pharmacokinetic model“. Archives of Disease in Childhood 104, Nr. 6 (17.05.2019): e44.2-e45. http://dx.doi.org/10.1136/archdischild-2019-esdppp.104.
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BackgroundLittle is known about fetal acetaminophen (paracetamol) pharmacokinetics and its potential for toxicity, despite the frequent use of acetaminophen during pregnancy. The aim of this study was to develop a feto-maternal physiologically based pharmacokinetic model (f-m PBPK) to predict placental transfer and PK of acetaminophen and its metabolites in fetus at term pregnancy.MethodsPreviously, a pregnancy PBPK model was developed for prediction of maternal PK of acetaminophen and its metabolites. This model was structurally extended with the fetal liver, and quantitative information on the maturation of relevant enzymes was integrated. Three different approaches (ex vivo placenta perfusion experiments, scaling of passive diffusion transfer rates, and the Mobi® default method) to describe placental drug transfer were tested. Predicted maternal and fetal acetaminophen concentrations were compared with those observed in the literature. umbilical cord data at birth.ResultsThe 3 different approaches to predicted acetaminophen PK in the umiblical vein were found to yield broadly similar results. Acetaminophen exposure was similar in maternal blood compared to venous umbilical cord blood. Prediction of the median dose fraction of acetaminophen converted to its metabolites (fm) revealed higher maternal acetaminophen-glucuronide formation clearance and sulphate formation compared to that in the fetal liver (fm_glucuronide52.2 vs 0% and fm_sulphate30.4 vs 0.8%, respectively) and higher fraction of acetaminophen converted to the reactive metabolite N-acetyl-p-benzoquinone-imine (fm_NAPQI, 6.5 vs 0.06%) in pregnant women compared to their fetus.ConclusionNo differences were observed in the 3 approaches for integration of placental drug transfer. Differences in acetaminophen biotransformation to its metabolites between pregnant women and their fetuses were quantitatively predicted.Disclosure(s)Paola Mian received a Short term Minor (STM-2017) grant from the Stichting Sophia Kinderziekenhuis fonds to conduct this research.
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Li, Yuezhe, A. Katharina Wilkins, Tim Knab und Joseph P. Boni. „Abstract 875: Quantitative systems pharmacology modeling of loncastuximab tesirine combined with mosunetuzumab and glofitamab helps guide dosing for patients with DLBCL“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 875. http://dx.doi.org/10.1158/1538-7445.am2024-875.
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Abstract Introduction: CD19 and CD20, B-lymphocyte surface antigens, are clinically validated therapeutic targets for the treatment of B-cell malignancies. Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]) is an antibody-drug conjugate comprising an anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer cytotoxin. Mosunetuzumab (Mosun) and glofitamab (Glofit) are CD20 × CD3 T-cell-engaging bispecific antibodies (bsAbs) that redirect T cells to eliminate malignant B cells. These agents target a different B-cell surface antigen than Lonca; hence, combining Lonca with either one of these bsAbs is expected to have additive or even synergistic efficacy. Previously, a novel physiologically-based pharmacokinetic (PBPK)-quantitative systems pharmacology (QSP) model was developed (Utsey K, et al. Clin Pharmacol Drug Dev. 2023;12:123-125) and validated with Lonca monotherapy clinical observations in R/R DLBCL (Caimi P, et al. Blood. 2022;140:9548-9550). Modeling results of Lonca in combination with Mosun or Glofit in R/R DLBCL are described herein. Methods: The model was based on the previously validated and published Lonca PBPK-QSP model. This model was reduced in physiological complexity to be compatible with a published minimal PBPK model of Mosun (Hosseini I, et al. NPJ Syst Biol Appl. 2020;6:28) while maintaining the core functionality of predicting tumor dynamics during Lonca monotherapy. The following assumptions were made: (1) Lonca or Mosun/Glofit induce healthy and malignant B-cell killing; (2) the tumor comprises malignant B cells and T cells; (3) tumor volume is calculated using malignant B-cell number; and (4) T cells can enter or leave the tumor as they enter or leave other tissues. Results: Improved tumor growth inhibition (TGI) should result from Lonca + bsAb combination therapy compared with any of the agents as monotherapy. While TGI was predicted to plateau by Cycle (C) 2 with Mosun and Glofit monotherapies, maximum activity of Lonca + bsAb combination therapies may not be observed until C4 or later. Additionally, predicted TGI increased with additional treatment cycles. Conclusions: Results indicate that treatment by the end of C3 for Lonca + Mosun and by the end of C4 for Lonca + Glofit would promote substantially more TGI compared with any of these agents alone. Increased doses of Lonca in combinations were predicted to have limited additional therapeutic benefit; however, additional cycles of combination treatment were predicted to increase TGI. This model suggests that Lonca doses could be reduced to allow for improved tolerability for longer periods of time, up to the point of maximal benefit, although clinical testing is needed to explore these results. The ongoing LOTIS-7 clinical trial (NCT04970901) evaluates the safety and anticancer activity of Lonca in combination with both Glofit and Mosun. Citation Format: Yuezhe Li, A Katharina Wilkins, Tim Knab, Joseph P. Boni. Quantitative systems pharmacology modeling of loncastuximab tesirine combined with mosunetuzumab and glofitamab helps guide dosing for patients with DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 875.
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Türk, Denise, Nina Hanke und Thorsten Lehr. „A Physiologically-Based Pharmacokinetic Model of Trimethoprim for MATE1, OCT1, OCT2, and CYP2C8 Drug–Drug–Gene Interaction Predictions“. Pharmaceutics 12, Nr. 11 (10.11.2020): 1074. http://dx.doi.org/10.3390/pharmaceutics12111074.
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Trimethoprim is a frequently-prescribed antibiotic and therefore likely to be co-administered with other medications, but it is also a potent inhibitor of multidrug and toxin extrusion protein (MATE) and a weak inhibitor of cytochrome P450 (CYP) 2C8. The aim of this work was to develop a physiologically-based pharmacokinetic (PBPK) model of trimethoprim to investigate and predict its drug–drug interactions (DDIs). The model was developed in PK-Sim®, using a large number of clinical studies (66 plasma concentration–time profiles with 36 corresponding fractions excreted in urine) to describe the trimethoprim pharmacokinetics over the entire published dosing range (40 to 960 mg). The key features of the model include intestinal efflux via P-glycoprotein (P-gp), metabolism by CYP3A4, an unspecific hepatic clearance process, and a renal clearance consisting of glomerular filtration and tubular secretion. The DDI performance of this new model was demonstrated by prediction of DDIs and drug–drug–gene interactions (DDGIs) of trimethoprim with metformin, repaglinide, pioglitazone, and rifampicin, with all predicted DDI and DDGI AUClast and Cmax ratios within 1.5-fold of the clinically-observed values. The model will be freely available in the Open Systems Pharmacology model repository, to support DDI studies during drug development.
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Marok, Fatima Zahra, Jan-Georg Wojtyniak, Laura Maria Fuhr, Dominik Selzer, Matthias Schwab, Johanna Weiss, Walter Emil Haefeli und Thorsten Lehr. „A Physiologically Based Pharmacokinetic Model of Ketoconazole and Its Metabolites as Drug–Drug Interaction Perpetrators“. Pharmaceutics 15, Nr. 2 (17.02.2023): 679. http://dx.doi.org/10.3390/pharmaceutics15020679.
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The antifungal ketoconazole, which is mainly used for dermal infections and treatment of Cushing’s syndrome, is prone to drug–food interactions (DFIs) and is well known for its strong drug–drug interaction (DDI) potential. Some of ketoconazole’s potent inhibitory activity can be attributed to its metabolites that predominantly accumulate in the liver. This work aimed to develop a whole-body physiologically based pharmacokinetic (PBPK) model of ketoconazole and its metabolites for fasted and fed states and to investigate the impact of ketoconazole’s metabolites on its DDI potential. The parent–metabolites model was developed with PK-Sim® and MoBi® using 53 plasma concentration-time profiles. With 7 out of 7 (7/7) DFI AUClast and DFI Cmax ratios within two-fold of observed ratios, the developed model demonstrated good predictive performance under fasted and fed conditions. DDI scenarios that included either the parent alone or with its metabolites were simulated and evaluated for the victim drugs alfentanil, alprazolam, midazolam, triazolam, and digoxin. DDI scenarios that included all metabolites as reversible inhibitors of CYP3A4 and P-gp performed best: 26/27 of DDI AUClast and 21/21 DDI Cmax ratios were within two-fold of observed ratios, while DDI models that simulated only ketoconazole as the perpetrator underperformed: 12/27 DDI AUClast and 18/21 DDI Cmax ratios were within the success limits.
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Pepin, Xavier J. H., Natalie J. Sanderson, Alexander Blanazs, Shveta Grover, Timothy G. Ingallinera und James C. Mann. „Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part I. Mechanistic modelling of drug product dissolution to derive a P-PSD for PBPK model input“. European Journal of Pharmaceutics and Biopharmaceutics 142 (September 2019): 421–34. http://dx.doi.org/10.1016/j.ejpb.2019.07.014.
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Fenneteau, F., J. Li, L. Couture, J. Turgeon und F. Nekka. „Prediction of the disposition of a P-gp substrate in wild-type and knockout mice tissues: Development of a physiologically based pharmacokinetic (PBPK) model and its global sensitivity analysis“. PAMM 7, Nr. 1 (Dezember 2007): 1121905–6. http://dx.doi.org/10.1002/pamm.200700608.
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Xie, Yuewu, Huixiang Liu, Xiaoyue Chen und Jie Xing. „The Effect of Gastric pH on the Pharmacokinetics-pharmacodynamics of Naphthoquine in Rodents, as well as in Human Predicted Using a PBPK Model“. Current Drug Metabolism 22, Nr. 5 (15.07.2021): 363–71. http://dx.doi.org/10.2174/1389200222666210129102411.
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Background: Fixed-dose combination of artemisinin and naphthoquine (NQ) is a new artemisinin- based combination therapy for the treatment of uncomplicated Plasmodium falciparum. NQ absorption has been reported to be affected by food in humans. Objectives: The effect of gastric pH on NQ pharmacokinetics and antiplasmodial activity was investigated. Methods: The pharmacokinetic profiles of NQ were studied in healthy rodents after an oral dose of NQ with or without gastric pH modulators, i.e., pentagastrin (stimulator) and famotidine (suppressant). The effect of gastric pH on NQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model. The effect of gastric pH on the antiplasmodial activity of NQ was evaluated in mice infected with Plasmodium yoelii. Results: Neither pentagastrin nor famotidine affected NQ absorption (AUC0-t and Cmax) significantly (P > 0.05) in rodents. The predicted PK profiles of NQ in humans did not show an effect of gastric pH. Compared to pure NQ (ED90, 1.2 mg/kg), the combination with pentagastrin showed non-significantly (< 1.5-fold) higher antimalarial potency (ED90, 1.1 mg/kg). Correspondingly, the elevation of gastric pH (up to pH 5) by famotidine treatment resulted in a relatively weaker antimalarial potency for NQ (ED90, 1.4 mg/kg). Such a difference is within the acceptable range of variability in NQ pharmacokinetics and antiplasmodial activity. Conclusions: Although the food was found to significantly impact NQ pharmacokinetics, other factors except for gastric pH should account for the result, and the warning of careful use of NQ in patients with the acid-related disease is not expected to be clinically meaningful.
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del Río, A., C. García-de-la-Mària, J. M. Entenza, O. Gasch, Y. Armero, D. Soy, C. A. Mestres et al. „Fosfomycin plus β-Lactams as Synergistic Bactericidal Combinations for Experimental Endocarditis Due to Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus“. Antimicrobial Agents and Chemotherapy 60, Nr. 1 (02.11.2015): 478–86. http://dx.doi.org/10.1128/aac.02139-15.
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ABSTRACTThe urgent need of effective therapies for methicillin-resistantStaphylococcus aureus(MRSA) infective endocarditis (IE) is a cause of concern. We aimed to ascertain thein vitroandin vivoactivity of the older antibiotic fosfomycin combined with different beta-lactams against MRSA and glycopeptide-intermediate-resistantS. aureus(GISA) strains. Time-kill tests with 10 isolates showed that fosfomycin plus imipenem (FOF+IPM) was the most active evaluated combination. In an aortic valve IE model with two strains (MRSA-277H and GISA-ATCC 700788), the following intravenous regimens were compared: fosfomycin (2 g every 8 h [q8h]) plus imipenem (1 g q6h) or ceftriaxone (2 g q12h) (FOF+CRO) and vancomycin at a standard dose (VAN-SD) (1 g q12h) and a high dose (VAN-HD) (1 g q6h). Whereas a significant reduction of MRSA-227H load in the vegetations (veg) was observed with FOF+IPM compared with VAN-SD (0 [interquartile range [IQR], 0 to 1] versus 2 [IQR, 0 to 5.1] log CFU/g veg;P= 0.01), no statistical differences were found with VAN-HD. In addition, FOF+IPM sterilized more vegetations than VAN-SD (11/15 [73%] versus 5/16 [31%];P= 0.02). The GISA-ATCC 700788 load in the vegetations was significantly lower after FOF+IPM or FOF+CRO treatment than with VAN-SD (2 [IQR, 0 to 2] and 0 [IQR, 0 to 2] versus 6.5 [IQR, 2 to 6.9] log CFU/g veg;P< 0.01). The number of sterilized vegetations after treatment with FOF+CRO was higher than after treatment with VAN-SD or VAN-HD (8/15 [53%] versus 4/20 [20%] or 4/20 [20%];P= 0.03). To assess the effect of FOF+IPM on penicillin binding protein (PBP) synthesis, molecular studies were performed, with results showing that FOF+IPM treatment significantly decreased PBP1, PBP2 (but not PBP2a), and PBP3 synthesis. These results allow clinicians to consider the use of FOF+IPM or FOF+CRO to treat MRSA or GISA IE.
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Dennison, James E., Philip L. Bigelow und Melvin E. Andersen. „Occupational exposure limits in the context of solvent mixtures, consumption of ethanol, and target tissue dose“. Toxicology and Industrial Health 20, Nr. 6-10 (Juli 2004): 165–75. http://dx.doi.org/10.1191/0748233704th203oa.
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Individuals are exposed to mixtures, and never to single chemicals. Depending on the composition of the elements of mixtures, significant toxicological interactions between the components may occur. These interactions are complex and often difficult to predict, ranging from synergistic to additive and subadditive interactions. The nature of the interactions needs to be evaluated as the target tissue dose of the active form of each chemical. PBPK modeling is an effective tool for determining the target tissue dose and evaluating these interactions when data are available for model development. Some of the interactions are pharmacokinetic in nature, affecting the disposition of other chemicals in the body. Other interactions can be pharmacodynamic in nature, altering the effects that other chemicals have on the organism. For many organic solvents, these interactions occur principally at the level of the metabolizing enzyme, cytochrome P-450 2E1 (CYP2E1). Many solvents are known to induce or inhibit CYP2E1, or both. Mixtures may be comprised of concomitant exposures to chemicals or from components encountered separately on-the-job, off-the-job, through the diet, and otherwise. Examples of mixtures where the exposure to separate components occurs off the job will be discussed, with special emphasis on ethanol consumption as a modifier of solvent pharmacokinetics. The present practice of the linear extrapolation of the toxicity of individual mixture components in the interpretation of occupational exposure limits will also be critiqued.
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Hu, Jing, Zhengbao Zhang, Senwei Lin, Qiuhuan Zhang, Guoxia Du, Ruishan Zhou, Xiaohan Qu, Guojiang Xu, Ying Yang und Yongming Cai. „Application of All-Ages Lead Model Based on Monte Carlo Simulation of Preschool Children’s Exposure to Lead in Guangdong Province, China“. Sustainability 15, Nr. 2 (06.01.2023): 1068. http://dx.doi.org/10.3390/su15021068.
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Introduction: Lead (Pb) poisoning in children is a major public health issue worldwide. The physiologically based pharmacokinetic model (PBPK model) has been extensively utilized in Pb exposure risk assessment and can connect external exposure with biological monitoring data. This study aimed to combine a Monte Carlo simulation with the all-ages lead model (ALLM) to quantify the heterogeneity and uncertainty of certain parameters in the population. The parameters of the all-ages lead model based on Monte Carlo simulation (ALLM + MC) were localized in Guangdong Province. Our study discusses the practicability of the application of the localized ALLM + MC in Guangdong Province. Methods: A local sensitivity analysis was used to assess the impact of pharmacokinetic parameters on the prediction of blood lead level (BLL). Environmental Pb concentration, exposure parameters, and sensitive parameters were included in the ALLM + MC, and the differences between the ALLM- and the ALLM + MC-predicted values were compared. Additionally, we localized the exposure parameters in the ALLM + MC and used them to evaluate BLL in preschool children from Guangdong Province. Finally, we compared the predictive values to those observed in the literature. Results: The predictive values of ALLM and ALLM + MC had a significant correlation (r = 0.969, p < 0.001). The predictive value of ALLM was included in the ALLM + MC prediction range. Moreover, there were no significant differences between the predictive and the observed values of preschool children from Guangdong Province (z = −0.319, p = 0.749). Except for children aged 5–6, the difference between the predictive and the observed values was less than 1 μg/dL. The root mean square error (RMSE) and the mean deviation (RMD) of ALLM and ALLM + MC were reduced by 24.73% and 32.83%, respectively. Conclusions: The localized ALLM + MC is more suitable for predicting the BLL of preschool children in Guangdong Province, which can be used to explain the heterogeneity and uncertainty of parameters in the population. The ALLM + MC has fewer time, space, and financial restrictions, making it more appropriate for determining the BLLs in large populations. The use of ALLM + MC would improve the feasibility of regular and long-term blood Pb detection.
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Ibrahim, A. H., H. Barry und C. M. Hughes. „A cross-sectional survey of general practitioners’ experiences with, views of, and attitudes towards, practice-based pharmacists“. International Journal of Pharmacy Practice 29, Supplement_1 (26.03.2021): i24—i25. http://dx.doi.org/10.1093/ijpp/riab015.029.
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Abstract Introduction Five-year pilot schemes were announced in both England and Northern Ireland (NI) to integrate practice-based pharmacists (PBPs) into general practices. The NI scheme anticipates that there will be 300 whole time equivalent PBPs in post by the end of the pilot (2020/2021).[1] There is little existing UK literature on PBPs’ role evolution and few studies have explored general practitioners’ (GPs) experiences of pharmacist integration into primary care practice. Aim To investigate GPs’ experiences with PBPs, their views about the PBP role and its impact upon patients and GPs, and their attitudes towards collaboration with PBPs. Methods A paper-based self-administered questionnaire was mailed to all general practices (n=329) across Northern Ireland (NI) on two occasions during September and October 2019, and was completed by one GP in every practice who had most contact with the PBP. The questionnaire was developed following a comprehensive literature review and comprised four sections (Table 1). Descriptive analyses were conducted using SPSS v26 and responses to open-ended questions were analysed thematically. Results The response rate was 61.7% (203/329). Respondents had a median age of 52.0 years and there was at least one PBP per general practice. All GPs had face-to-face meetings with PBPs, with three-quarters (78.7%, n=159) meeting with the PBP more than once a week. GPs reported that two-thirds of PBPs (62.4%, n=126) were qualified as independent prescribers, with 76.2% of prescribers (n=96) currently prescribing for patients. The most common PBP activities were medication reconciliation and medication reviews. The majority of GPs reported that PBPs always/very often had the required clinical skills (83.6%, n=162) and knowledge (87.0%, n=167) to provide safe and effective care for patients. However, only 31.1% (n=61) stated that PBPs sometimes had the confidence to make clinical decisions. The majority of GPs (>85%) displayed largely positive attitudes towards collaboration with PBPs. Most respondents agreed/strongly agreed that PBPs will have a positive impact on patient outcomes (95.0%, n=192) and can provide a better link between general practices and community pharmacists (96.1%, n=194). However, 24.8% of GPs (n=50) were unclear if the PBP role moved community pharmacists to the periphery of the primary care team. Thematic analysis of the open comments indicated that GPs were in favour of more PBP sessions and full-time posts. Conclusion This study has revealed that the majority of GPs had positive views and attitudes about the PBP role, its impact in primary care and collaboration with PBPs. The findings may have implications for future developments in order to extend integration of PBPs within general practice, including the enhancement of training in clinical skills and decision-making. Our target sample included all general practices within NI and the response rate enhanced generalisability at the practice level. However, the study sample was limited to NI, and some findings may not be relevant to other parts of the UK. Further work is required to explore PBPs’, community pharmacists’ and patients’ views of this role in general practice to corroborate study findings. References 1. Strategic Leadership Group for Pharmacy. Practice-based pharmacists' statement. 2016. (Online) Available at: https://www.health-ni.gov.uk/sites/default/files/publications/health/practice-based-pharmacists.pdf (accessed 06 Oct 2020). 2. Van C, Costa D, Mitchell B, Abbott P, Krass I. Development and validation of a measure and a model of general practitioner attitudes toward collaboration with pharmacists. Res Soc Adm Pharm. 2013; 9(6): 688–699.
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Jayawardena, Thilina U., Lei Wang, K. K. Asanka Sanjeewa, Sang In Kang, Jung-Suck Lee und You-Jin Jeon. „Antioxidant Potential of Sulfated Polysaccharides from Padina boryana; Protective Effect against Oxidative Stress in In Vitro and In Vivo Zebrafish Model“. Marine Drugs 18, Nr. 4 (14.04.2020): 212. http://dx.doi.org/10.3390/md18040212.
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Elevated levels of reactive oxygen species (ROS) damage the internal cell components. Padina boryana, a brown alga from the Maldives, was subjected to polysaccharide extraction. The Celluclast enzyme assisted extract (PBE) and ethanol precipitation (PBP) of P. boryana were assessed against hydrogen peroxide (H2O2) induced cell damage and zebra fish models. PBP which contains the majority of sulfated polysaccharides based on fucoidan, showed outstanding extracellular ROS scavenging potential against H2O2. PBP significantly declined the intracellular ROS levels, and exhibited protection against apoptosis. The study revealed PBPs’ ability to activate the Nrf2/Keap1 signaling pathway, consequently initiating downstream elements such that catalase (CAT) and superoxide dismutase (SOD). Further, ROS levels, lipid peroxidation values in zebrafish studies were declined with the pre-treatment of PBP. Collectively, the results obtained in the study suggest the polysaccharides from P. boryana might be a potent source of water soluble natural antioxidants that could be sustainably utilized in the industrial applications.
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Audi, Said H., Anthony Cammarata, Anne V. Clough, Ranjan K. Dash und Elizabeth R. Jacobs. „Quantification of mitochondrial membrane potential in the isolated rat lung using rhodamine 6G“. Journal of Applied Physiology 128, Nr. 4 (01.04.2020): 892–906. http://dx.doi.org/10.1152/japplphysiol.00789.2019.
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Mitochondrial membrane potential (Δψm) plays a key role in vital mitochondrial functions, and its dissipation is a hallmark of mitochondrial dysfunction. The objective of this study was to develop an experimental and computational approach for estimating Δψm in intact rat lungs using the lipophilic fluorescent cationic dye rhodamine 6G (R6G). Rat lungs were excised and connected to a ventilation-perfusion system. The experimental protocol consisted of three single-pass phases, loading, washing, and uncoupling, in which the lungs were perfused with R6G-containing perfusate, fresh R6G-free perfusate, or R6G-free perfusate containing the mitochondrial uncoupler FCCP, respectively. This protocol was carried out with lung perfusate containing verapamil vehicle or verapamil, an inhibitor of the multidrug efflux pump P-glycoprotein (Pgp). Results show that the addition of FCCP resulted in an increase in R6G venous effluent concentration and that this increase was larger in the presence of verapamil than in its absence. A physiologically based pharmacokinetic (PBPK) model for the pulmonary disposition of R6G was developed and used for quantitative interpretation of the kinetic data, including estimating Δψm. The estimated value of Δψm [−144 ± 24 (SD) mV] was not significantly altered by inhibiting Pgp with verapamil and is comparable with that estimated previously in cultured pulmonary endothelial cells. These results demonstrate the utility of the proposed approach for quantifying Δψm in intact functioning lungs. This approach has potential to provide quantitative assessment of the effect of injurious conditions on lung mitochondrial function and to evaluate the impact of therapies that target mitochondria. NEW & NOTEWORTHY A novel experimental and computational approach for estimating mitochondrial membrane potential (Δψm) in intact functioning lungs is presented. The isolated rat lung inlet-outlet concentrations of the fluorescent cationic dye rhodamine 6G were measured and analyzed by using a computational model of its pulmonary disposition to determine Δψm. The approach has the potential to provide quantitative assessment of the effect of injurious conditions and their therapies on lung mitochondrial function.
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Tudora, Anabella, und Franz-Josef Hambsch. „Parameterisation of the residual temperature distribution based on the modelling of successive emission of prompt neutrons“. EPJ Web of Conferences 169 (2018): 00025. http://dx.doi.org/10.1051/epjconf/201816900025.
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A new deterministic modelling taking into account the successive emission of prompt neutrons from initial fragments of a fragmentation range {A, Z, TKE} constructed as in the Point-by-Point (PbP) treatment is described. The good agreement of different prompt emission quantities obtained from this modelling (e.g. v(A), v(TKE), E-γ(A), E-γ(TKE), etc.) with the experimental data and the results of the PbP model and other Monte-Carlo models validates the present modelling of sequential emission. The distributions of different residual quantities, including the residual temperature distributions P(T) of light and heavy fragments allow to obtain a new parameterisation of P(T) which can be used in the PbP model and the Los Alamos model.
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Shea, T. C., J. R. Mason, A. M. Storniolo, B. Newton, M. Breslin, M. Mullen, D. M. Ward, L. Miller, M. Christian und R. Taetle. „Sequential cycles of high-dose carboplatin administered with recombinant human granulocyte-macrophage colony-stimulating factor and repeated infusions of autologous peripheral-blood progenitor cells: a novel and effective method for delivering multiple courses of dose-intensive therapy.“ Journal of Clinical Oncology 10, Nr. 3 (März 1992): 464–73. http://dx.doi.org/10.1200/jco.1992.10.3.464.
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PURPOSE The trial was undertaken to study the effect of administering granulocyte-macrophage colony-stimulating factor (GM-CSF) with and without peripheral-blood progenitor cells (PBPC) on the hematologic and nonhematologic toxicity observed with multiple cycles of high-dose carboplatin chemotherapy. PATIENTS AND METHODS Eighteen patients with a variety of solid tumors received a total of 40 cycles of carboplatin, 1,200 mg/m2 per cycle, administered by continuous infusion over 96 hours. All 40 courses were administered with a daily 4-hour intravenous (IV) infusion of either 5 or 10 micrograms/kg/d of recombinant human Escherichia coli-derived GM-CSF. The first 20 courses were administered without PBPC support (treatment A). Because of severe neutropenia and thrombocytopenia, the next 20 courses of therapy were administered with GM-CSF, PBPC, and oral antibiotic prophylaxis (treatment B). RESULTS The addition of PBPC support led to a significant reduction in the duration of neutropenia (10.5 v 7.5 days; P = .027) and thrombocytopenia (12.4 v 5.2 days; P = .001), number of RBC transfusions (six v three; P = .01) and platelet transfusions (10.3 v 3.7; P = .013), number of hospital days (12.6 v 2.9; P = .01), and days of IV antibiotics (11.8 v 2.4; P = .007) per cycle. Significant increases in the weekly dose intensity (206 v 285 mg/m2/wk; P = .014) and total dose (2,287 v 3,600 mg/m2; P = .018) of carboplatin delivered were also observed with treatment B. The overall response rate in this study was 70%, with 11 of 16 assessable patients achieving either a complete (three patients) or partial (eight patients) remission. CONCLUSION This combination of GM-CSF and PBPC infusion represents an effective method for delivering multiple cycles of high-dose carboplatin chemotherapy and may serve as a model for the administration of high-dose chemotherapy in future trials.
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Kallidaikurichi Srinivasan, Karthikeyan, Anthony Gallagher, Niall O’Brien, Vinod Sudir, Nick Barrett, Raymund O’Connor, Francesca Holt, Peter Lee, Brian O’Donnell und George Shorten. „Proficiency-based progression training: an ‘end to end’ model for decreasing error applied to achievement of effective epidural analgesia during labour: a randomised control study“. BMJ Open 8, Nr. 10 (Oktober 2018): e020099. http://dx.doi.org/10.1136/bmjopen-2017-020099.
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BackgroundTraining procedural skills using proficiency-based progression (PBP) methodology has consistently resulted in error reduction. We hypothesised that implementation of metric-based PBP training and a valid assessment tool would decrease the failure rate of epidural analgesia during labour when compared to standard simulation-based training.MethodsDetailed, procedure-specific metrics for labour epidural catheter placement were developed based on carefully elicited expert input. Proficiency was defined using criteria derived from clinical performance of experienced practitioners. A PBP curriculum was developed to train medical personnel on these specific metrics and to eliminate errors in a simulation environment.Seventeen novice anaesthetic trainees were randomly allocated to undergo PBP training (Group P) or simulation only training (Group S). Following training, data from the first 10 labour epidurals performed by each participant were recorded. The primary outcome measure was epidural failure rate.ResultsA total of 74 metrics were developed and validated. The inter-rater reliability (IRR) of the derived assessment tool was 0.88. Of 17 trainees recruited, eight were randomly allocated to group S and six to group P (three trainees did not complete the study). Data from 140 clinical procedures were collected. The incidence of epidural failure was reduced by 54% with PBP training (28.7% in Group S vs 13.3% in Group P, absolute risk reduction 15.4% with 95% CI 2% to 28.8%, p=0.04).ConclusionProcedure-specific metrics developed for labour epidural catheter placement discriminated the performance of experts and novices with an IRR of 0.88. Proficiency-based progression training resulted in a lower incidence of epidural failure compared to simulation only training.Trial registration numberNCT02179879.NCT02185079; Post-results.
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Hanke, Nina, Sebastian Frechen, Daniel Moj, Hannah Britz, Thomas Eissing, Thomas Wendl und Thorsten Lehr. „PBPK Models for CYP3A4 and P-gp DDI Prediction: A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin“. CPT: Pharmacometrics & Systems Pharmacology 7, Nr. 10 (07.09.2018): 647–59. http://dx.doi.org/10.1002/psp4.12343.
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Zubair, Abba, Rhonda Grant, Han Tun, Candido Rivera, Alvaro Moreno-aspitia, Vivek Roy, Gerry Colon-Otero und Lawrence Solberg. „Platelet Count Is a Sensitive Predictor of Bone Marrow Reserve and Autologous Peripheral Blood Progenitor Cell Mobilization.“ Blood 106, Nr. 11 (16.11.2005): 5280. http://dx.doi.org/10.1182/blood.v106.11.5280.5280.
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Abstract Background: Previous studies have proposed combination of various factors that predict poor mobilization after GCSF stimulation. However, there is no single clinical or laboratory test that reliably correlates with bone marrow reserve and PBPC mobilization. Peripheral blood CD34+ cell count (pCD34) reliably correlates with PBPC mobilization and yield but only after GCSF administration. Methods: We have prospectively followed 36 autologous PBPC transplant candidates, from the time of initial evaluation to transplant, to evaluate factors the correlate with bone marrow reserve and autologous PBPC mobilization. Results: The patients median age was 63 (range 26 – 76). 21 of the 36 patients were diagnosed with dysproteinemia, primarily multiple myeloma, 10 patients had non-Hodgkin’s lymphoma while the remaining 5 had other form of hematological malignancies. Our evaluation shows baseline platelet count prior to growth factor administration significantly correlate with total CD34+ cell yield (spearman: r = 0.64, p <0.001, Figure 1). In addition, daily platelet count during PBPC harvest correlate with CD34+ cell yield for the day (spearman: r = 0.6, p <0.001). Using multiple linear regression model (F = 19.1, p <0.001, R2 = 0.64), we have determined patients’ age (p = 0.03) and type of disease (p <0.001), in addition to platelet count (p<0.001), significantly correlate with total CD34+ cell yield. Further analysis showed low baseline platelet count predicts poor PBPC mobilization. Using Receiver Operating Curve (ROC), we have determined that platelet count of 174,000/ul was the best cut-off for collecting at least 2 million/Kg CD34+ cells with sensitivity of 81% and specificity of 78% and estimated correct classification of 81%. Even though pCD34 counts were slightly more sensitive and were better at identifying poor mobilizers in our cohort (best cut-off 10/ul, sensitivity 96%, specificity 67%, correct classification 89%), their clinical utility were diminished since the values were only known after GCSF administration. Conclusion: Baseline platelet count is a sensitive predictor of bone marrow reserve and can be used prior to growth factor administration to predict poor mobilization. Figure 1: Correlation of baseline platelet count and total CD34+ cell yield Figure 1:. Correlation of baseline platelet count and total CD34+ cell yield
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Liu, Xingbang, und Yong He. „Effect and Clinical Value of Protective Motivation Intervention Rehabilitation Model on Pain Perception and Dysfunction in Patients with Lumbar Disc Herniation: Based on a Retrospective Cohort Study“. Computational and Mathematical Methods in Medicine 2022 (30.08.2022): 1–8. http://dx.doi.org/10.1155/2022/5911889.
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Objective. To examine the potential medical benefits of protective motivation intervention rehabilitation mode on pain perception and dysfunction in patients with lumbar disc herniation (LDH). Methods. 140 LDH patients hospitalized from January 2021 to September 2021 were totally selected. The control group received regular rehabilitation, and the research group received protective motivation intervention rehabilitation. The comparisons of scores of disease knowledge, visual analogue scale (VAS), pain belief and perception scale (PBPI), Japanese Orthopedic Association Score (JOA), Roland-Morris dysfunction (RMDQ), and quality of life scale (SF-36) were made across different groups. Results. The scores of disease knowledge in the two cohorts at 1 month, 2 months, and 3 months after intervention were greater than those before intervention, and the difference is statistically significant ( P < 0.05 ). The scores of VAS, PBPI, JOA, and RMDQ at 1 month, 2 months, and 3 months after intervention were downregulated. At 1 month, 2 months, and 3 months after intervention, the experimental scores of VAS, PBPI, JOA, and RMDQ were markedly fewer than the control group, and the difference is statistically significant ( P < 0.05 ). The scores of SF-36 after intervention were statistically upregulated, and the difference is statistically significant ( P < 0.05 ). After intervention, the score of SF-36 in the research group was significantly higher than that in the control group, and the difference is statistically significant ( P < 0.05 ). Conclusion. The application of protective motivation intervention in rehabilitation of LDH patients can more effectively improve their cognitive level, reduce their pain perception, improve their lumbar function, and enhance their well-being.
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Weaver, CH, B. Hazelton, R. Birch, P. Palmer, C. Allen, L. Schwartzberg und W. West. „An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy“. Blood 86, Nr. 10 (15.11.1995): 3961–69. http://dx.doi.org/10.1182/blood.v86.10.3961.bloodjournal86103961.
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The CD34 antigen is expressed by committed and uncommitted hematopoietic progenitor cells and is increasingly used to assess stem cell content of peripheral blood progenitor cell (PBPC) collections. Quantitative CD34 expression in PBPC collections has been suggested to correlate with engraftment kinetics of PBPCs infused after myeloablative therapy. We analyzed the engraftment kinetics as a function of CD34 content in 692 patients treated with high-dose chemotherapy (HDC). Patients had PBPCs collected after cyclophosphamide based mobilization chemotherapy with or without recombinant human granulocyte colony-stimulating factor (rhG-CSF) until > or = 2.5 x 10(6) CD34+ cells/kg were harvested. Measurement of the CD34 content of PBPC collections was performed daily by a central reference laboratory using a single technique of CD34 analysis. Forty-five patients required a second mobilization procedure to achieve > or = 2.5 x 10(6) CD34+ cells/kg and 15 patients with less than 2.5 x 10(6) CD34+ cells/kg available for infusion received HDC. A median of 9.94 x 10(6) CD34+ cells/kg (range, 0.5 to 112.6 x 10(6) CD34+ cells/kg) contained in the PBPC collections was subsequently infused into patients after the administration of HDC. Engraftment was rapid with patients requiring a median of 9 days (range, 5 to 38 days) to achieve a neutrophil count of 0.5 x 10(9)/L and a median of 9 days (range, 4 to 53+ days) to achieve a platelet count of > or = 20 x 10(9)/L. A clear dose-response relationship was evident between the number of CD34+ cells per kilogram infused between the number of CD34+ cells per kilogram infused and neutrophil and platelet engraftment kinetics. Factors potentially influencing the engraftment kinetics of neutrophil and platelet recovery were examined using a Cox regression model. The single most powerful mediator of both platelet (P = .0001) and neutrophil (P = .0001) recovery was the CD34 content of the PBPC product. Administration of a post-PBPC infusion myeloid growth factor was also highly correlated with neutrophil recovery (P = .0001). Patients receiving high-dose cyclophosphamide, thiotepa, and carboplatin had more rapid platelet recovery than patients receiving other regimens (P = .006), and patients requiring 2 mobilization procedures versus 1 mobilization procedure to achieve > or = 2.5 x 10(6) CD34+ cells/kg experienced slower platelet recovery (P = .005). Although a minimal threshold CD34 dose could not be defined, > or = 5.0 x 10(6) CD34+ cells/kg appears to be optimal for ensuring rapid neutrophil and platelet recovery.
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Glass, Bertram, Lutz Uharek, Matthias Zeis, Peter Dreger, Helmut Löffler, Jörg Steinmann und Norbert Schmitz. „Allogeneic Peripheral Blood Progenitor Cell Transplantation in a Murine Model: Evidence for an Improved Graft-Versus-Leukemia Effect“. Blood 90, Nr. 4 (15.08.1997): 1694–700. http://dx.doi.org/10.1182/blood.v90.4.1694.
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Abstract Peripheral blood progenitor cells (PBPCs) are increasingly being used to replace bone marrow cells (BMCs) as a source of hematopoietic stem cells also in the field of allogeneic transplantation. Whereas it is well known that PBPC grafts and BM differ significantly in progenitor cell content and lymphocyte dose, the clinical consequences of these differences with respect to engraftment, graft-versus-host disease (GVHD), and the graft-versus-leukemia (GVL) effect are more difficult to assess. We present a murine model that allows us to evaluate engraftment, GVHD, and GVL effect of allogeneic PBPC transplantation (PBPCT). Balb/c mice (H-2d) served as recipients. Donors were major histocompatibility complex-matched DBA/2 mice or syngeneic Balb/c mice, respectively. Experiments with increasing numbers of BMCs or Filgastrim-mobilized PBPCs showed that the number of progenitor cells in the graft was correlated with the probability to engraft, irrespective of the graft type. With identically high cell numbers transferred (1 × 109 nucleated cells/kg body weight [BW]), the mortality rates due to GVHD (25%) were about the same after allogeneic BM transplantation (BMT) and allogeneic PBPCT, although PBPC grafts contained four times more CD3+ T cells as compared with BM grafts (6.2 × 108v 1.4 × 108/kg BW). For investigation of GVL activity, Balb/c recipients were injected with syngeneic cells of the B-lymphocytic leukemia cell line A20 2 days before transplantation. After total body irradiation to a dose of 7.5 Gy, 1 × 109/kg BW Balb/c PBPCs, DBA BMCs, or DBA PBPCs were infused. The relapse rates observed were 80% after syngeneic PBPCT (n = 22), 60% after allogeneic BMT (n = 23), and 34% after allogeneic PBPCT (n = 26) (allogeneic BMT v PBPCT, P = .032). We conclude that transplantation of allogeneic PBPCs instead of BM may enhance the GVL effect without an increase of GVHD.
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Glass, Bertram, Lutz Uharek, Matthias Zeis, Peter Dreger, Helmut Löffler, Jörg Steinmann und Norbert Schmitz. „Allogeneic Peripheral Blood Progenitor Cell Transplantation in a Murine Model: Evidence for an Improved Graft-Versus-Leukemia Effect“. Blood 90, Nr. 4 (15.08.1997): 1694–700. http://dx.doi.org/10.1182/blood.v90.4.1694.1694_1694_1700.
Annotation:
Peripheral blood progenitor cells (PBPCs) are increasingly being used to replace bone marrow cells (BMCs) as a source of hematopoietic stem cells also in the field of allogeneic transplantation. Whereas it is well known that PBPC grafts and BM differ significantly in progenitor cell content and lymphocyte dose, the clinical consequences of these differences with respect to engraftment, graft-versus-host disease (GVHD), and the graft-versus-leukemia (GVL) effect are more difficult to assess. We present a murine model that allows us to evaluate engraftment, GVHD, and GVL effect of allogeneic PBPC transplantation (PBPCT). Balb/c mice (H-2d) served as recipients. Donors were major histocompatibility complex-matched DBA/2 mice or syngeneic Balb/c mice, respectively. Experiments with increasing numbers of BMCs or Filgastrim-mobilized PBPCs showed that the number of progenitor cells in the graft was correlated with the probability to engraft, irrespective of the graft type. With identically high cell numbers transferred (1 × 109 nucleated cells/kg body weight [BW]), the mortality rates due to GVHD (25%) were about the same after allogeneic BM transplantation (BMT) and allogeneic PBPCT, although PBPC grafts contained four times more CD3+ T cells as compared with BM grafts (6.2 × 108v 1.4 × 108/kg BW). For investigation of GVL activity, Balb/c recipients were injected with syngeneic cells of the B-lymphocytic leukemia cell line A20 2 days before transplantation. After total body irradiation to a dose of 7.5 Gy, 1 × 109/kg BW Balb/c PBPCs, DBA BMCs, or DBA PBPCs were infused. The relapse rates observed were 80% after syngeneic PBPCT (n = 22), 60% after allogeneic BMT (n = 23), and 34% after allogeneic PBPCT (n = 26) (allogeneic BMT v PBPCT, P = .032). We conclude that transplantation of allogeneic PBPCs instead of BM may enhance the GVL effect without an increase of GVHD.
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Schiedlmeier, B., K. Kühlcke, H. G. Eckert, C. Baum, W. J. Zeller und S. Fruehauf. „Quantitative assessment of retroviral transfer of the human multidrug resistance 1 gene to human mobilized peripheral blood progenitor cells engrafted in nonobese diabetic/severe combined immunodeficient mice“. Blood 95, Nr. 4 (15.02.2000): 1237–48. http://dx.doi.org/10.1182/blood.v95.4.1237.
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Mobilized peripheral blood progenitor cells (PBPC) are a potential target for the retrovirus-mediated transfer of cytostatic drug-resistance genes. We analyzed nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse-repopulating CD34+ PBPC from patients with cancer after retroviral transduction in various cytokine combinations with the hybrid vector SF-MDR, which is based on the Friend mink cell focus-forming/murine embryonic stem-cell virus and carries the human multidrug resistance 1 (MDR1) gene. Five to 13 weeks after transplantation of CD34+ PBPC into NOD/SCID mice (n = 84), a cell dose-dependent multilineage engraftment of human leukocytes up to an average of 33% was observed. The SF-MDR provirus was detected in the bone marrow (BM) and in its granulocyte fractions in 96% and 72%, respectively, of chimeric NOD/SCID mice. SF-MDR provirus integration assessed by quantitative real-time polymerase chain reaction (PCR) was optimal in the presence of Flt-3 ligand/thrombopoietin/stem-cell factor, resulting in a 6-fold (24% ± 5% [mean ± SE]) higher average proportion of gene-marked human cells in NOD/SCID mice than that achieved with IL-3 alone (P < .01). A population of clearly rhodamine-123dull human myeloid progeny cells could be isolated from BM samples from chimeric NOD/SCID mice. On the basis of PCR and rhodamine-123 efflux data, up to 18% ± 4% of transduced cells were calculated to express the transgene. Our data suggest that the NOD/SCID model provides a valid assay for estimating the gene-transfer efficiency to repopulating human PBPC that may be achievable in clinical autologous transplantation. P-glycoprotein expression sufficient to prevent marrow aplasia in vivo may be obtained with this SF-MDR vector and an optimized transduction protocol.
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Gubanova, M. V., N. N. Kushnarenko und T. M. Karavaeva. „Clinical significance of 24-hour blood pressure monitoring in prediction of hypertension development in patients with gout“. Siberian Journal of Clinical and Experimental Medicine 36, Nr. 3 (07.10.2021): 104–10. http://dx.doi.org/10.29001/2073-8552-2021-36-3-104-110.
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Aim. The aim of the study was to develop the model for establishing early diagnosis of hypertension in patients with gout. The model was based on data of 24-hour blood pressure monitoring.Material and Methods. A total of 69 patients with gout were enrolled in a single-stage cross-sectional prospective study. Three study groups were assigned as follows: group 1 (main group) comprised hypertensive men with gout (n = 41); group 2 (comparison group) comprised normotensive men with gout (n = 28); group 3 (control) included relatively healthy men (n = 30). Daily blood pressure monitoring was performed on an outpatient basis using a BPLab device (Peter Telegin, Russia).Results. The significant intergroup differences were found in the following parameters: lowest, mean, and highest 24-hour systolic blood pressure (SBP) values in patients of main and comparison groups (р < 0.001) and in patients of main and control groups (р < 0.001); mean and maximum 24-hour diastolic blood pressure (DBP) values in patients of main and comparison groups (р < 0.001) and in patients of main and control groups (р < 0.001); lowest, mean, and highest 24-hour pulse blood pressure (PBP) values in patients of main and comparison groups (р < 0.001) and in patients of main and control groups (р < 0.001); mean, and maximum 24-hour PBP values in patients of comparison and control groups (р < 0.001). Median values of the lowest, mean, and highest 24-hour SBP in hypertensive patients with gout were significantly higher than the corresponding values in normotensive patients with gout and healthy men of group 3 (p < 0.001). Median values of mean and maximum 24-hour DBP in main group were higher than the corresponding values in comparison group and control group (p < 0.001). Median values of the lowest, mean, and highest 24-hour PBP in hypertensive patients with gout exceeded the corresponding values of patients of control group (p < 0.001). Median values of the mean and maximum 24-hour PBP in main group exceeded the corresponding values of patients of comparison group (p < 0.001). Based on the binary logistic regression model, the prognostic algorithm for hypertension development in gout patients was created using the parameters of 24-hour blood pressure monitoring as predictors and the cut-off K value. If the value of K was > 0.54, then the hypertension development was predicted in gout patients. The sensitivity of developed diagnostic model was 0.84, and the specificity was 0.95.Conclusion. Тhe proposed model, based on the assessment of average-daily values of the lowest, mean, and highest SBP, allowed to establish early diagnosis of hypertension in patients with gout with the accuracy of up to 90%.
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Seeger, Timon, Marlon Veldwijk, Gary Bridger, Gary Calandra, Hartmut Goldschmidt, Anthony Ho und Stefan Fruehauf. „The CXCR4 Antagonist AMD3100 Mobilizes a More Primitive Subset of CD34+ Cells Than G-CSF.“ Blood 106, Nr. 11 (16.11.2005): 1969. http://dx.doi.org/10.1182/blood.v106.11.1969.1969.
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Abstract The CXCR4-antagonist AMD3100 mobilizes peripheral blood progenitor cells (PBPC) in 8–10 hours while a standard mobilization regimen with granulocyte colony-stimulating factor (G-CSF) takes 4 days before significant numbers of PBPC can be detected. Recently it was shown that AMD3100-mobilized PBPC have a higher reconstitution potential in the NOD/SCID mouse model than G-CSF mobilized PBPC. Clinically they also mediate rapid and sustained engraftment after transplantation. Prospective comparative studies are yet lacking. It can be expected that the functional differences are also reflected on the phenotypic level. We used 6-color and 3-color flow cytometry to study the co-expression of primitive and lineage-associated markers on mobilized PBPC of patients with multiple myeloma and non-Hodgkin’s lymphoma (n=5). Mobilization treatment consisted of 5 days G-CSF (10 μg/kg, s.c. AM) and a single dose of AMD3100 (240 μg/kg, s.c.) in the evening of day 4. CD34+ cells of day 4, before AMD3100-dosing (G-CSF group) and on day 5, 10-hours after AMD3100 (AMD3100+G-CSF group) were compared. Primitive CD34+/CD38- cells which solely mediate hematopoietic reconstitution in the NOD/SCID mouse model were increased after addition of AMD3100 in all patients by a median of 2,58 fold (range 1,19–6,66) while the myeloid lineage committed CD34+/CD117+ and the actively proliferating CD34+/CD71+ cell subsets were significantly downregulated (p<0,05 each). The myeloid CD34+/CD33+ cell population showed a similar trend (median 0,60-fold change, range 0,24–1,08). Adhesion molecules were significantly regulated (CD49b) or showed such a trend (CD49d). Quantification of aldehyde dehydrogenase (AlDH) positive cells in A+G vs. G-CSF-mobilized samples did not show significant differences between these groups. We conclude that AMD3100 mobilizes a more primitive subset of CD34+ progenitor cells than G-CSF alone. Whether this translates into lower CD34+ threshold values for transplantation to achieve a similarly rapid and sustained engraftment after transplantation or into a shorter reconstitution period if similar amounts of CD34+ cells are used as after standard G-CSF-mobilization needs further study. CD34 coexpression analysis: AMD3100+G-CSF mobilized CD34+ cells/G-CSF mobilized CD34+ cells (fold-change) CD34+/ median min max P value CD38− 2.58 1.19 2.09 0.073 HLA-DR− 1.14 0.14 2.09 0.568 CD90+ 0.42 0.05 26.47 0.417 CD7+ 1.17 0.58 2.9 0.433 CD10+ 0.87 0.11 6.66 0.513 CD19+ 1.11 0.72 12.69 0.368 CD33+ 0.6 0.24 1.08 0.075 CD45RA+ 5.84 1.54 7.46 0.155 CD71+ 0.51 0.43 0.64 0.002 CD117+ 0.36 0.02 1.11 0.046 CD18+ 1.55 0.56 4.09 0.347 CD49b+ 6.91 2.74 11.75 0.08 CD49d+ 0.63 0.25 0.89 0.061 CD58+ 5.82 2.83 21.88 0.261 CD62L 2.9 1.43 4.36 0.419 CD184+ 0.99 0.25 1.79 0.955
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Goldberg, Joel, Christopher Bethel, Andrea M. Hujer, Steven Marshall, Magdalena A. Taracila, Krisztina M. Papp-Wallce, Vijay Kumar, Focco van den Akker, Mark Plummer und Robert A. Bonomo. „1256. In Vivo Activity and Structural Characterization of a New Generation γ-Lactam Siderophore Antibiotic Against Multidrug-Resistant Gram-Negative Bacteria and Acinetobacter spp“. Open Forum Infectious Diseases 7, Supplement_1 (01.10.2020): S645. http://dx.doi.org/10.1093/ofid/ofaa439.1440.
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Abstract Background Multidrug-resistant (MDR) A. baumannii presents a critical need for innovative antibacterial development. We have identified a new series of γ-lactam (oxopyrazole) antibiotics that target penicillin binding proteins (PBPs) and incorporate a siderophore moiety to facilitate periplasmic uptake. YU253911, an advanced iteration of this class shows potent in vitro activity against clinically relevant Gram-negative organisms including Acinetobacter spp. Methods Minimum inhibitory concentrations (MICs) for YU253911 were determined using broth microdilution against a 198-member panel of clinical isolates of Acinetobacter spp. Resistant strains were further evaluated for susceptibility to YU253911 in combination with sulbactam. The antibiotic’s target protein was evaluated by binding studies with Bocillin™, a fluorescent penicillin analogue, and modeled in the PBP active site. YU253911 was evaluated in vivo in a mouse soft tissue infection model. Results MIC testing for YU253911 revealed an MIC50 of 0.5 μg/mL and an MIC90 of 16 μg/mL, which compared favorably to all tested β-lactam antibiotics including penicillins, cephalosporins, monobactams and carbapenems (MIC50 = 2 to > 16 μg/mL). Combination with sulbactam augmented the activity of the agent. There was no apparent correlation between YU253911-resistance and the presence of specific β-lactamase genes, and incubation with representative β-lactamase proteins (KPC-2, OXA-23, OXA-24, PER-2, PDC-3, NDM-1, VIM-2, and IMP-1) showed negligible hydrolysis of the agent. YU253911 showed promising preclinical pharmacokinetics in mice with a 15 h half-life from intravenous administration and demonstrated a dose-dependent reduction in colony forming units from 50 and 100 mg/kg q6h dosing in a mouse thigh infection model using P. aeruginosa. Conclusion YU253911, a new generation γ-lactam antibiotic effective against MDR A. baumannii demonstrated promising in in vitro potency and favorable pharmacokinetics which correlated with in vivo efficacy. Disclosures Krisztina M. Papp-Wallce, PhD, Entasis (Grant/Research Support)Merck (Grant/Research Support)Venatorx (Grant/Research Support) Robert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support)
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Wilmsmeier, Lisa, Jeannine Von Der Born, Rizky I. Sugianto, Carl Grabitz, Bernhard Mw Schmidt, Ana Celine Braun, Denise Homeyer, Uwe Tegtbur und Anette Melk. „SIGNIFICANT INCREASES IN PERIPHERAL AND CENTRAL BLOOD PRESSURE IN CHILDREN AT MUCH LOWER BODY MASS INDEX THAN EXPECTED“. Journal of Hypertension 42, Suppl 1 (Mai 2024): e11. http://dx.doi.org/10.1097/01.hjh.0001019420.16281.8a.
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Objective: Cardiovascular (CV) complications are the most common causes of death worldwide. Increased body weight and higher blood pressure (BP) are known risk factors for CV disease with a known association of higher body mass index (BMI) with higher BP. Our study intended to describe at which BMI-level significant increases in either central (cBP) or peripheral BP (pBP) can be detected in young children. Design and method: We measured cBP and pBP in 1,183 schoolchildren (first/second graders; mean age 7.9±0.6 years; 51% male). pBP measurements were performed with a validated oscillometric device (Dinamap-VC150-GE). cBP was measured noninvasively with the Mobil-O-Graph (IEM). Multivariable linear regression models (corrected for age, sex, height) were used to compare pBP/cBP values of children with a BMI<50th percentile (pct) with children separated in five groups according to BMI pct (>=50th-<65thpct; >=65th-<75thpct; >=75th-<85thpct; >=85th-<95thpct; >=95thpct). Results: BMI was 17±3 kg/m2 (M±SD), 275 children (22.8%) were overweight (BMI>=85th pct), 126 (10.5%) obese (BMI>=95thpct). Peripheral systolic blood pressure (pSBP) was 104±8mmHg (M±SD), peripheral diastolic blood pressure (pDBP) 61±6mmHg (M±SD); 5% of the cohort displayed hypertensive pBP values >=95thpct. In the unadjusted analysis, we saw an increase in pSBP (Fig.1A) and cSBP (Fig.1B) already at a BMI around 60thpct. Further analysis comparing the corrected means revealed that pSBP showed already a significant increase for children with a BMI>=75thpct (ß=1.8, p=0.026) when compared to children with a BMI<50thpct. For the model including pDBP no significant effects were seen. cSBP significantly increased already in children with a BMI >=65thpct. (ß=1.7, p=0.031), while cDBP increased significantly in children with a BMI >=75thpct (ß=1.5; p=0.012) when compared to children with a BMI<50thpct. Conclusions: Our findings suggest that increases in body weight affect pBP and particularly cBP at much lower BMI pct level than expected. These results are alarming as pediatricians usually get concerned at BMI levels above the 85thpct (defined as cut-off for overweight in children based on WHO growth reference values). Given the important interaction between both risk factors and their track from childhood to adulthood, effective overweight prevention must take place in early childhood.