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https://www.readbyqxmd.com/read/28936957/-pk-pd-of-vancomycin-in-patients-with-severe-acute-pancreatitis-combined-with-augmented-renal-clearance
#1
Juan He, Enqiang Mao, Feng Jing, Huiting Jiang, Wenyun Xu, Wanhua Yang, Erzhen Chen
OBJECTIVE: To evaluate the serum trough concentration and the pharmacokinetics/pharmacodynamics (PK/PD) of vancomycin in patients with severe acute pancreatitis (SAP), and analyze the effect of vancomycin continuous infusion for optimizing the characteristics of its PK/PD. METHODS: The inhospital patients with SAP received vancomycin treatment and admitted to emergency intensive care unit (EICU) of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine from January 2011 to December 2016 were enrolled...
September 2017: Zhonghua Wei Zhong Bing Ji Jiu Yi Xue
https://www.readbyqxmd.com/read/28933618/novel-cns-drug-discovery-and-development-approach-model-based-integration-to-predict-neuro-pharmacokinetics-and-pharmacodynamics
#2
Elizabeth C M de Lange, Willem van den Brink, Yumi Yamamoto, Wilhelmus E A de Witte, Yin Cheong Wong
CNS drug development has been hampered by inadequate consideration of CNS pharmacokinetic (PK), pharmacodynamics (PD) and disease complexity (reductionist approach). Improvement is required via integrative model-based approaches. Areas covered: The authors summarize factors that have played a role in the high attrition rate of CNS compounds. Recent advances in CNS research and drug discovery are presented, especially with regard to assessment of relevant neuro-PK parameters. Suggestions for further improvements are also discussed...
September 21, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28933595/phosphoproteome-based-kinase-activity-profiling-reveals-the-critical-role-of-map2k2-and-plk1-in-neuronal-autophagy
#3
Lei-Lei Chen, Yong-Bo Wang, Ju-Xian Song, Wan-Kun Deng, Jia-Hong Lu, Li-Li Ma, Chuan-Bin Yang, Min Li, Yu Xue
Recent studies have demonstrated that dysregulation of macroautophagy/autophagy may play a central role in the pathogenesis of neurodegenerative disorders, and the induction of autophagy protects against the toxic insults of aggregate-prone proteins by enhancing their clearance. Thus, autophagy has become a promising therapeutic target against neurodegenerative diseases. In this study, quantitative phosphoproteomic profiling together with a computational analysis was performed to delineate the phosphorylation signalling networks regulated by 2 natural neuroprotective autophagy enhancers, corynoxine (Cory) and corynoxine B (Cory B)...
September 21, 2017: Autophagy
https://www.readbyqxmd.com/read/28928866/ct-721-a-potent-bcr-abl-inhibitor-exhibits-excellent-in-vitro-and-in-vivo-efficacy-in-the-treatment-of-chronic-myeloid-leukemia
#4
Yinghui Sun, Na Zhao, Huan Wang, Qiong Wu, Yunqi Han, Qichao Liu, Mangang Wu, Yuliang Liu, Fansheng Kong, He Wang, Ying Sun, Deguang Sun, Lutao Jing, Guojing Tang, Yuandong Hu, Dengming Xiao, Hong Luo, Yongxin Han, Yong Peng
Kinase inhibitors that target Bcr-Abl are highly effective in the treatment of chronic myeloid leukemia (CML). However, these inhibitors are often invalidated due to the drug resistance. Therefore, the discovery and development of novel Bcr-Abl inhibitors is required to overwhelm the drug resistance in the treatment of CML resistant to the currently used first-line Bcr-Abl inhibitors. Herein we have described a newly developed Bcr-Abl inhibitor CT-721, which displayed potent inhibitory effects on wild-type and T315I mutant Bcr-Abl...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28927793/discovery-of-n-substituted-7-azaindoles-as-pan-pim-kinase-inhibitors-lead-series-identification-part-ii
#5
Claude Barberis, Neil Moorcroft, James Pribish, Elina Tserlin, Alexandre Gross, Mark Czekaj, Matthieu Barrague, Paul Erdman, Tahir Majid, Joseph Batchelor, Mikhail Levit, Andrew Hebert, Liduo Shen, Sandra Moreno-Mazza, Anlai Wang
N-Substituted azaindoles have been discovered as pan-PIM kinase inhibitors. Initial SAR, early ADME and PK/PD data of a series of compounds is described and led to the identification of promising pan-PIM inhibitors which validated our interest in the 7-azaindole scaffold and led us to pursue the identification of a clinical candidate.
September 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28921890/phase-ii-study-of-dabigatran-in-children-with-venous-thrombosis-pharmacokinetics-safety-and-tolerabilty
#6
J M L Halton, M Albisetti, B Biss, L Bomgaars, M Brueckmann, S Gropper, R Harper, F Huang, M Luciani, H Maas, I Tartakovsky, L G Mitchell
BACKGROUND: The current standard-of-care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option. OBJECTIVES: To assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of DE oral liquid formulation (OLF) in pediatric patients with VTE. PATIENTS/METHODS: Patients who had completed planned treatment with low-molecular-weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2-<12 and 1-<2 years) and received DE OLF based on an age- and weight-adjusted nomogram...
September 16, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28918591/platform-model-describing-pharmacokinetic-properties-of-vc-mmae-antibody-drug-conjugates
#7
Matts Kågedal, Leonid Gibiansky, Jian Xu, Xin Wang, Divya Samineni, Shang-Chiung Chen, Dan Lu, Priya Agarwal, Bei Wang, Ola Saad, Neelima Koppada, Bernard M Fine, Jin Y Jin, Sandhya Girish, Chunze Li
Antibody-drug conjugates (ADCs) developed using the valine-citrulline-MMAE (vc-MMAE) platform, consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile vc linker. Recently, clinical data for a variety of vc-MMAE ADCs has become available. The goal of this analysis was to develop a platform model that simultaneously described antibody-conjugated MMAE (acMMAE) pharmacokinetic (PK) data from eight vc-MMAE ADCs, against different targets and tumor indications; and to assess differences and similarities of model parameters and model predictions, between different compounds...
September 16, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28918129/where-do-substrates-of-diacylglycerol-kinases-come-from-diacylglycerol-kinases-utilize-diacylglycerol-species-supplied-from-phosphatidylinositol-turnover-independent-pathways
#8
REVIEW
Fumio Sakane, Satoru Mizuno, Daisuke Takahashi, Hiromichi Sakai
Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprises ten isozymes (α-κ) and regulates a wide variety of physiological and pathological events, such as cancer, type II diabetes, neuronal disorders and immune responses. DG and PA consist of various molecular species that have different acyl chains at the sn-1 and sn-2 positions, and consequently, mammalian cells contain at least 50 structurally distinct DG/PA species. Because DGK is one of the components of phosphatidylinositol (PI) turnover, the generally accepted dogma is that all DGK isozymes utilize 18:0/20:4-DG derived from PI turnover...
September 9, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28916830/the-effects-of-different-enrofloxacin-dosages-on-clinical-efficacy-and-resistance-development-in-chickens-experimentally-infected-with-salmonella-typhimurium
#9
Jun Li, Haihong Hao, Guyue Cheng, Xu Wang, Saeed Ahmed, Muhammad Abu Bakr Shabbir, Zhenli Liu, Menghong Dai, Zonghui Yuan
To investigate the optimal dosage which can improve clinical efficacy and minimize resistance, pharmacokinetics/pharmacodynamics model of enrofloxacin was established. Effect of enrofloxacin treatments on clearance of Salmonella in experimentally infected chickens and simultaneously resistance selection in Salmonella and coliforms were evaluated in three treatment groups (100, PK/PD designed dosage of 4, 0.1 mg/kg b.w.) and a control group. Treatment duration was three rounds of 7-day treatment alternated with 7-day withdrawal...
September 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28913853/dose-rationalisation-of-pembrolizumab-and-nivolumab-using-pharmacokinetic-modelling-and-simulation-and-cost-analysis
#10
Kayode Ogungbenro, Alkesh Patel, Robert Duncombe, Richard Nuttall, James Clark, Paul Lorigan
Pembrolizumab and nivolumab are highly selective anti PD-1 antibodies approved for the treatment of advanced malignancies. Variable exposure and significant wastage have been associated with body size dosing of monoclonal antibodies. The following dosing strategies were evaluated using simulations: body weight, dose banding, fixed dose and pharmacokinetics based method. The relative cost to body weight dosing for band, fixed 150 mg and 200 mg, and pharmacokinetics derived strategies were -15%, -25%, +7% and -16% for pembrolizumab and -8%, -6%, and -10% for band, fixed, and pharmacokinetics derived strategies for nivolumab...
September 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28910514/pharmacokinetics-of-single-dose-ceftaroline-fosamil-in-children-with-cystic-fibrosis
#11
Jennifer Le, John S Bradley, Sara Hingtgen, Shannon Skochko, Nanette Black, Ronald N Jones, Meerana Lim, Edmund V Capparelli
BACKGROUND: Single-dose pharmacokinetics (PK) and safety of ceftaroline fosamil with population pharmacokinetic/pharmacodynamic (PK/PD) modeling for staphylococcal pneumonia was performed in children with CF. METHODS: Subjects between 6 and 18 years old were evaluated in this phase 1, open-label, single-dose, prospective study using 10 mg/kg (up to 600 mg). Non-compartmental analysis and population-based PK analyses with Monte Carlo simulation (for doses 8-20 mg/kg every 8 h, infused over 1-4 h) were conducted...
September 14, 2017: Pediatric Pulmonology
https://www.readbyqxmd.com/read/28905667/preliminary-pharmacokinetics-of-intravenous-and-subcutaneous-dolasetron-and-pharmacodynamics-of-subcutaneous-dolasetron-in-healthy-cats
#12
Andrea K Herndon, Jessica M Quimby, Liberty G Sieberg, Leigh Davis, Amber L Caress, Sabina Ligas, Ryan J Hansen, Luke A Wittenburg, Danial L Gustafson
Objectives The objectives were to evaluate the pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) dolasetron and the pharmacodynamics (PDs) of SC dolasetron in healthy cats. Methods Five cats with unremarkable complete blood count, serum biochemistry and urinalyses were utilized. In the PK study, cats received 0.8 mg/kg SC and IV dolasetron in a crossover format. Serum samples were obtained via a jugular catheter at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h after the administration of dolasetron...
September 1, 2017: Journal of Feline Medicine and Surgery
https://www.readbyqxmd.com/read/28902711/triggering-of-inflammasome-by-impaired-autophagy-in-response-to-acute-experimental-parkinson-s-disease-involvement-of-the-pi3k-akt-mtor-pathway
#13
Sabrina Giacoppo, Placido Bramanti, Emanuela Mazzon
Several lines of evidence suggest that the inflammasome activation is involved in the progression of neurodegenerative diseases. However, the relation between Parkinson's disease (PD) and the inflammasome is still unclear. This study was designed to assess the involvement of inflammasome in acute experimental PD. Specifically, acute PD was induced in C57BL/6 mice by an injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At seven days from MPTP induction, mice were euthanized and the midbrains were sampled to carry out immunohistochemical evaluations and western blot analysis...
September 11, 2017: Neuroreport
https://www.readbyqxmd.com/read/28899515/the-water-extract-of-liuwei-dihuang-possesses-multi-protective-properties-on-neurons-and-muscle-tissue-against-deficiency-of-survival-motor-neuron-protein
#14
Yu-Ting Tseng, Yuh-Jyh Jong, Wei-Fang Liang, Fang-Rong Chang, Yi-Ching Lo
BACKGROUND: Deficiency of survival motor neuron (SMN) protein, which is encoded by the SMN1 and SMN2 genes, induces widespread splicing defects mainly in spinal motor neurons, and leads to spinal muscular atrophy (SMA). Currently, there is no effective treatment for SMA. Liuwei dihuang (LWDH), a traditional Chinese herbal formula, possesses multiple therapeutic benefits against various diseases via modulation of the nervous, immune and endocrine systems. Previously, we demonstrated water extract of LWDH (LWDH-WE) protects dopaminergic neurons and improves motor activity in models of Parkinson's disease...
October 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28895785/preclinical-pharmacokinetic-characterization-of-an-adipose-tissue-targeting-monoclonal-antibody-in-obese-and-non-obese-animals
#15
Sharmila Rajan, Danielle Mandikian, Amos Baruch, Thomas R Gelzleichter, Dale Stevens, Junichiro Sonoda, Kyra Cowan, C Andrew Boswell, Eric Stefanich
Target receptor levels can influence pharmacokinetics (PK) or pharmacodynamics (PD) of monoclonal antibodies (mAbs), and can affect drug development of this class of molecules. We generated an effector-less humanized bispecific antibody that selectively activates fibroblast growth factor receptor (FGFR)1 and βKlotho receptor, a FGF21 receptor complex highly expressed in both white and brown adipocytes. The molecule shows cross-species binding with comparable equilibrium binding affinity (Kd) for human, cynomolgus monkey, and mouse FGFR1/βKlotho...
September 12, 2017: MAbs
https://www.readbyqxmd.com/read/28892591/a-pilot-dose-finding-study-of-etanercept-in-rheumatoid-arthritis
#16
Ferdinand C Breedveld, Heather E Jones, Kim Peifer, Joan Korth-Bradley
A randomized, parallel-dose study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of etanercept in 61 patients with rheumatoid arthritis (RA) who received doses from 10 mg once-weekly to 50 mg twice-weekly for 4 weeks. Empiric application of a maximal-effect (Emax ) model to pooled steady-state concentrations (Css ) and PD markers provided half-maximal-effect concentration estimates of 567, 573, 465, 87, and 159 ng/mL for change from baseline in number of swollen joints, number of painful joints, erythrocyte sedimentation rate, interleukin-6, and matrix metalloproteinase-3, respectively...
September 11, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28890509/proposed-pharmacokinetic-pharmacodynamic-breakpoint-of-garenoxacin-and-other-quinolones
#17
Yuka Yamagishi, Tatsuya Shibata, Satoshi Nakagawa, Nobuhiko Nomura, Junichi Mitsuyama, Hiroshige Mikamo
The pharmacokinetic-pharmacodynamic (PK-PD) breakpoints (BPs) of garenoxacin (GRNX) and other oral quinolones were calculated using the Monte Carlo simulation (MCS) based on the distribution of changes in their plasma concentrations. PK-PD BPs of 400 mg once a day (QD) of GRNX for the free area under the curve/minimum inhibitory concentration (fAUC/MIC) for 30 of Streptococcus pneumoniae and 100 of Gram-negative bacteria: (G (-)) were 0.5 and 0.125 μg/mL, respectively. PK-PD BPs of other quinolones for S. pneumoniae/G(-) were 1/0...
September 11, 2017: Japanese Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28888484/prediction-of-human-efficacious-antidepressant-doses-using-the-mouse-forced-swim-test
#18
Eunice Yuen, Steven Swanson, Jeffrey M Witkin
The forced swim test (FST) is a commonly used preclinical animal behavioural model for prediction of antidepressant activity in humans. While the FST may qualitatively predict efficacy, less is known about the quantitative translation of FST data to human efficacious doses. Assessing quantitative translation allows better predictions of human efficacious doses and a higher chance of success in the drug development process. Dose-response and time-course FST experiments were carried out on mice using four marketed antidepressants (citalopram, desipramine, bupropion, desvenlafaxine) in addition to ketamine, all with varying mechanisms of action...
September 6, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28888218/impact-of-non-adherence-on-the-safety-and-efficacy-of-uric-acid-lowering-therapies-in-the-treatment-of-gout
#19
Daniel Hill-McManus, Elena Soto, Scott Marshall, Steven Lane, Dyfrig Hughes
AIMS: Dual-urate lowering therapy (ULT) with xanthine oxidase inhibitor and uricosuric medications is a treatment option for severe gout. Uricosurics can cause hyperuricosuria, a risk factor for nephrolithiasis and acute uric acid nephropathy. The aims of this study were to simulate the relation between suboptimal drug adherence and efficacy, and to quantify the risk of hyperuricosuria in gout patients receiving mono and dual-ULTs. METHODS: The impact of poor medication adherence was studied using 2-compartment PK models based on published evidence and a semi-mechanistic, 4-compartment pharmacodynamic (PD) model...
September 9, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28884437/extrapolation-of-a-brivaracetam-exposure-response-model-from-adults-to-children-with-focal-seizures
#20
Rik Schoemaker, Janet R Wade, Armel Stockis
INTRODUCTION: Prediction of brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for brivaracetam to children, using an existing population PK model for brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration-effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A). METHODS: The existing adult PK/PD model for brivaracetam was applied to a combined adult-pediatric dataset of levetiracetam...
September 7, 2017: Clinical Pharmacokinetics
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