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https://www.readbyqxmd.com/read/29236228/population-pharmacokinetic-pharmacodynamic-modeling-of-ropivacaine-in-spinal-anesthesia
#1
Zoubir Djerada, Catherine Feliu, Yoann Cazaubon, Faouzi Smati, Philippe Gomis, Dominique Guerrot, Beny Charbit, Olivier Fernandes, Jean-Marc Malinovsky
BACKGROUND: Ropivacaine is frequently used in spinal anesthesia but the relationship between plasma concentrations and sensory block level remains unknown. OBJECTIVE: The aim of this study was to assess the relationship between plasma ropivacaine concentrations and effects during spinal anesthesia. METHODS: Sixty patients aged between 18 and 82 years were included in this study after providing written informed consent. Patients were randomly assigned to receive intrathecal administration of ropivacaine 15, 20 or 25 mg...
December 13, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29236223/transit-and-lifespan-in-neutrophil-production-implications-for-drug-intervention
#2
Daniel Câmara De Souza, Morgan Craig, Tyler Cassidy, Jun Li, Fahima Nekka, Jacques Bélair, Antony R Humphries
A comparison of the transit compartment ordinary differential equation modelling approach to distributed and discrete delay differential equation models is studied by focusing on Quartino's extension to the Friberg transit compartment model of myelosuppression, widely relied upon in the pharmaceutical sciences to predict the neutrophil response after chemotherapy, and on a QSP delay differential equation model of granulopoiesis. An extension to the Quartino model is provided by considering a general number of transit compartments and introducing an extra parameter that allows for the decoupling of the maturation time from the production rate of cells...
December 13, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29233651/identification-of-bicyclic-hexafluoroisopropyl-alcohol-sulfonamides-as-retinoic-acid-receptor-related-orphan-receptor-gamma-ror%C3%AE-rorc-inverse-agonists-employing-structure-based-drug-design-to-improve-pregnane-x-receptor-pxr-selectivity
#3
Hua Gong, David S Weinstein, Zhonghui Lu, James J-W Duan, Sylwia Stachura, Lauren Haque, Ananta Karmakar, Hemalatha Hemagiri, Dhanya Kumar Raut, Arun Kumar Gupta, Javed Khan, Dan Camac, John S Sack, Andrew Pudzianowski, Dauh-Rurng Wu, Melissa Yarde, Ding-Ren Shen, Virna Borowski, Jenny H Xie, Huadong Sun, Celia D'Arienzo, Marta Dabros, Michael A Galella, Faye Wang, Carolyn A Weigelt, Qihong Zhao, William Foster, John E Somerville, Luisa M Salter-Cid, Joel C Barrish, Percy H Carter, T G Murali Dhar
We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies...
December 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29232954/efficacy-and-safety-profiles-of-oral-atorvastatin-loaded-nanoparticles-effect-of-size-modulation-on-biodistribution
#4
Iman S Ahmed, Rania El Hosary, Mariame A Hassan, Mohamed Haider, Marwa M Abd-Rabo
Atorvastatin calcium (AC)-loaded nanoparticles (NPs) of mean particle diameter < 100 nm and narrow distribution were prepared and characterized. Their in-vivo PK as well as PD measures following oral administration in different dosage regimens in hyperlipidemic rats were evaluated. The results revealed that the oral bioavailability of two selected AC-NPs formulations was 235% and 169% relative to Lipitor®. However, the treatment regimens were not superior in reducing serum total cholesterol (TC), low-density lipoproteins (LDL) and triglycerides (TG) levels compared to Lipitor®...
December 12, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29229637/elucidating-the-pharmacokinetics-pharmacodynamics-of-aerosolized-colistin-against-multidrug-resistant-acinetobacter-baumannii-and-klebsiella-pneumoniae-in-a-mouse-lung-infection-model
#5
Yu-Wei Lin, Qi Tony Zhou, Mei-Ling Han, Ke Chen, Nikolas J Onufrak, Jiping Wang, John D Turnidge, Benjamin P Howden, Alan Forrest, Hak-Kim Chan, Jian Li
Pharmacokinetics/pharmacodynamics (PK/PD) of aerosolized colistin was investigated against Acinetobacter baumannii and Klebsiella pneumoniae over 24 h in a neutropenic mouse lung infection model. Dose fractionation studies were performed over 2.64 to 23.8 mg/kg/day, and the data were fitted to a sigmoid inhibitory model. AUC/MIC in the epithelial lining fluid was the most predictive PK/PD index for aerosolized colistin against both pathogens. Our study provides important pharmacological information for optimizing aerosolized colistin...
December 11, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29229429/semi-mechanistic-pharmacokinetic-pharmacodynamic-modelling-of-antibiotic-drug-combinations
#6
REVIEW
Margreke J E Brill, Anders N Kristoffersson, Chenyan Zhao, Elisabet I Nielsen, Lena E Friberg
BACKGROUND: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic/pharmacodynamic (PK/PD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens...
December 8, 2017: Clinical Microbiology and Infection
https://www.readbyqxmd.com/read/29226626/randomized-clinical-study-of-safety-pharmacokinetics-and-pharmacodynamics-of-ripk1-inhibitor-gsk2982772-in-healthy-volunteers
#7
Kathleen Weisel, Nicola E Scott, Debra J Tompson, Bartholomew J Votta, Sujith Madhavan, Kat Povey, Allen Wolstenholme, Monica Simeoni, Todd Rudo, Lauren Richards-Peterson, Tarjinder Sahota, J Gene Wang, John Lich, Joshua Finger, Adeline Verticelli, Michael Reilly, Peter J Gough, Philip A Harris, John Bertin, Mei-Lun Wang
GSK2982772 is a highly selective inhibitor of receptor-interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first-in-human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo-controlled, double-blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1-120 mg) or placebo in a crossover design during each of 4 treatment periods...
December 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29218011/pharmacogenetic-variation-in-over-100-genes-in-patients-receiving-acenocumarol
#8
Vanessa Gonzalez-Covarrubias, Javier Urena-Carrion, Beatriz Villegas-Torres, J Eduardo Cossío-Aranda, Sergio Trevethan-Cravioto, Raul Izaguirre-Avila, O Javier Fiscal-López, Xavier Soberon
Coumarins are widely prescribed worldwide, and in Mexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on CYP2C8, CYP2C19, CYP4F11, CYP4F2, PROS, and GGCX, VKORC1, CYP2C18, NQO1. A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, CYP1A1, CYP3A4, CYP3A5, and F8, and a low proportion of novel-to-known variants on CYP2E1, VKORC1, and SULT1A1/2...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29209222/pk-pd-analysis-of-marbofloxacin-against-streptococcus-suis-in-pigs
#9
Zhixin Lei, Qianying Liu, Bing Yang, Haseeb Khaliq, Jiyue Cao, Qigai He
Marbofloxacin is a fluoroquinolone antibiotic and highly effective treatment for respiratory diseases. Here we aimed to evaluate the ex vivo activity of marbofloxacin against Streptococcus suis in pig serum, as well as the optimal dosages scheme for avoiding the fluoroquinolone resistance development. A single dose of 8 mg/kg body weight (bw) was administrated orally to healthy pigs and serum samples were collected during the next 72 h. Serum marbofloxacin content was determined by high-performance liquid chromatography...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29209208/the-clinical-pharmacokinetics-and-pharmacodynamics-of-warfarin-when-combined-with-compound-danshen-a-case-study-for-combined-treatment-of-coronary-heart-diseases-with-atrial-fibrillation
#10
Chunxiao Lv, Changxiao Liu, Zhuhua Yao, Xiumei Gao, Lanjun Sun, Jia Liu, Haibo Song, Ziqiang Li, Xi Du, Jinxia Sun, Yanfen Li, Kui Ye, Ruihua Wang, Yuhong Huang
Warfarin is used as anticoagulant and Compound Danshen prescription (CDP) is able to promote blood circulation. The combination might produce a synergic effect for patients of coronary heart diseases (CHDs) with atrial fibrillation (AF). Whether the combination increases the bleeding risk of warfarin is unclear, so the effects of Compound Danshen dripping pill (CDDP) on the pharmacokinetics (PK) and pharmacodynamics (PD) profiles of warfarin was investigated in patients. The dose and blood concentrations of warfarin, the four indicators of blood coagulation, prothrombin time, activated partial thromboplatin time, thrombin time, fibrinogen, and international normalized ratio value were compared when with and without CDDP treatment...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29203492/extreme-drug-tolerance-of-mycobacterium-tuberculosis-in-caseum
#11
Jansy P Sarathy, Laura E Via, Danielle Weiner, Landry Blanc, Helena Boshoff, Eliseo A Eugenin, Clifton E Barry, Véronique A Dartois
Tuberculosis (TB) recently became the leading infectious cause of death in adults, while attempts to shorten therapy have largely failed. Dormancy, persistence and drug tolerance are among the factors driving the long therapy duration. Assays to measure in situ drug susceptibility of Mycobacterium tuberculosis (Mtb) bacteria in pulmonary lesions are needed if we are to discover new fast acting regimens and address the global TB threat. Here we take a first step towards this goal and describe an ex vivo assay developed to measure the cidal activity of anti-TB drugs against Mtb bacilli present in cavity caseum, obtained from rabbits with active TB...
December 4, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29203480/pharmacodynamics-of-the-long-acting-echinocandin-cd101-in-the-neutropenic-invasive-candidiasis-murine-model-using-an-extended-interval-dosing-design
#12
Alexander J Lepak, Miao Zhao, B VanScoy, Paul G Ambrose, David R Andes
Echinocandins are important in the prevention and treatment of invasive candidiasis but limited by current dosing regimens that include daily intravenous administration. The novel echinocandin CD101 has a prolonged half-life of approximately 130 h in humans making it possible to design once-weekly dosing strategies. The current study examined the pharmacodynamic activity of CD101 using the neutropenic invasive candidiasis mouse model against select C. albicans (n=4), C. glabrata (n=3), and C. parapsilosis (n=3) strains...
December 4, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29202215/pharmacokinetics-pharmacodynamics-safety-and-tolerability-of-dabigatran-etexilate-oral-liquid-formulation-in-infants-with-venous-thromboembolism
#13
Jacqueline M L Halton, Anne-Caroline Picard, Ruth Harper, Fenglei Huang, Martina Brueckmann, Savion Gropper, Hugo Maas, Igor Tartakovsky, Ildar Nurmeev, Lesley G Mitchell, Leonardo R Brandão, Elizabeth Chalmers, Manuela Albisetti
Venous thromboembolism (VTE) is more frequent in infants than in older children. Treatment guidelines in children are adapted from adult VTE data, but do not currently include direct oral anticoagulant use. Dabigatran etexilate (DE) use in the paediatric population with VTE therefore requires verification. We investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship, safety and tolerability of DE oral liquid formulation (OLF) in infants with VTE (aged < 12 months) who had completed standard anticoagulant treatment in an open-label, phase IIa study...
November 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/29195829/importance-of-vancomycin-loading-doses-in-intermittent-infusion-regimens
#14
Martin Šíma, Jan Hartinger, Tereza Cikánková, Ondřej Slanař
PURPOSE: Delayed achievement of target vancomycin serum concentrations may adversely affect clinical outcomes. The objective of this retrospective study was to explore the real frequency of loading dose use and to evaluate the impact of loading dose for the achievement of vancomycin PK/PD target in adult patients treated with intermittent vancomycin. As a secondary aim we determined optimal vancomycin loading dose based on individual pharmacokinetic calculations. METHODS: Vancomycin pharmacokinetic models were computed using two-compartmental analysis...
November 28, 2017: Journal of Infection and Chemotherapy: Official Journal of the Japan Society of Chemotherapy
https://www.readbyqxmd.com/read/29193126/pharmacokinetics-and-pharmacodynamics-of-azeloprazole-sodium-a-novel-proton-pump-inhibitor-in-healthy-japanese-volunteers
#15
Ryoko Toda, Masanari Shiramoto, Emi Komai, Kazuyoshi Yoshii, Masamichi Hirayama, Yoshihiro Kawabata
The pharmacokinetics (PK) and pharmacodynamics (PD) of proton pump inhibitors differ among cytochrome P450 (CYP) 2C19 genotypes. Therefore, we developed azeloprazole sodium (Z-215), a novel proton pump inhibitor, whose metabolism is not affected by CYP2C19 activity in vitro. However, the PK and PD of azeloprazole sodium have not been evaluated in Japanese subjects. We conducted an open-label, crossover study in healthy Japanese male volunteers to evaluate the plasma concentration and intragastric pH with respect to CYP2C19 genotype after repeated administration of 10, 20, and 40 mg azeloprazole sodium and 10 and 20 mg rabeprazole sodium (rabeprazole)...
November 28, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29191916/duvelisib-a-novel-oral-dual-inhibitor-of-pi3k-%C3%AE-%C3%AE-is-clinically-active-in-advanced-hematologic-malignancies
#16
Ian W Flinn, Susan O'Brien, Brad Kahl, Manish Patel, Yasuhiro Oki, Francine F Foss, Pierluigi Porcu, Jeffrey Jones, Jan A Burger, Nitin Jain, Virginia M Kelly, Kerstin Allen, Mark Douglas, Jennifer Sweeney, Patrick Kelly, Steven Horwitz
Duvelisib (IPI-145) is a novel, oral, dual inhibitor of phosphoinositide 3-kinase (PI3K)-δ and PI3K-γ in late-stage clinical development for treatment of hematologic malignancies. This Phase 1 study (registered as NCT01476657 at ClinicalTrials.gov) evaluated the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of duvelisib in 210 patients with advanced hematologic malignancies. In the Dose Escalation Phase (n=31), duvelisib 8 to 100 mg BID was administered, with MTD determined to be 75 mg BID...
November 30, 2017: Blood
https://www.readbyqxmd.com/read/29190188/biomeasures-and-mechanistic-modeling-highlight-pk-pd-risks-for-a-monoclonal-antibody-targeting-fn14-in-kidney-disease
#17
Xiaoying Chen, Vahid Farrokhi, Pratap Singh, Mireia Fernandez Ocana, Jenil Patel, Lih-Ling Lin, Hendrik Neubert, Joanne Brodfuehrer
Discovery of the upregulation of fibroblast growth factor-inducible-14 (Fn14) receptor following tissue injury has prompted investigation into biotherapeutic targeting of the Fn14 receptor for the treatment of conditions such as chronic kidney diseases. In the development of monoclonal antibody (mAb) therapeutics, there is an increasing trend to use biomeasures combined with mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling to enable decision making in early discovery. With the aim of guiding preclinical efforts on designing an antibody with optimized properties, we developed a mechanistic site-of-action (SoA) PK/PD model for human application...
November 30, 2017: MAbs
https://www.readbyqxmd.com/read/29180278/higher-versus-standard-amikacin-single-dose-in-emergency-department-patients-with-severe-sepsis-and-shock-a-randomized-controlled-trial
#18
Sabrina De Winter, Joost Wauters, Wouter Meersseman, Jan Verhaegen, Eric Van Wijngaerden, Willy Peetermans, Pieter Annaert, Sandra Verelst, Isabel Spriet
BACKGROUND: Recent studies suggest that ICU patients treated with amikacin frequently do not attain the PK/PD target, i.e. a peak above minimal inhibitory concentration (MIC) ratio of at least 8, when a single dose of 15 mg/kg is used. No data are available for patients admitted to the emergency department (ED). The aim of this study was to determine PK/PD target attainment in patients presenting with severe sepsis or septic shock and treated with 15 vs. 25 mg/kg of amikacin. METHODS: This prospective randomized controlled study was undertaken in ED patients admitted with severe sepsis or septic shock...
November 24, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/29180135/alpha-synuclein-transgenic-mice-h-%C3%AE-synl62-display-%C3%AE-syn-aggregation-and-a-dopaminergic-phenotype-reminiscent-of-parkinson-s-disease
#19
Silke Frahm, Valeria Melis, David Horsley, Janet E Rickard, Gernot Riedel, Paula Fadda, Maria Scherma, Charles R Harrington, Claude M Wischik, Franz Theuring, Karima Schwab
Alpha-Synuclein (α-Syn) accumulation is considered a major risk factor for the development of synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies. We have generated mice overexpressing full-length human α-Syn fused to a membrane-targeting signal sequence under the control of the mouse Thy1-promotor. Three separate lines (L56, L58 and L62) with similar gene expression levels, but considerably heightened protein accumulation in L58 and L62, were established. In L62, there was widespread labelling of α-Syn immunoreactivity in brain including spinal cord, basal forebrain, cortex and striatum...
November 24, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/29178491/pharmacokinetic-and-pharmacodynamic-modeling-of-serum-etrolizumab-and-circulating-%C3%AE-7-receptor-occupancy-in-patients-with-ulcerative-colitis
#20
Xiaohui Wei, Leonid Gibiansky, Yehong Wang, Franklin Fuh, Rich Erickson, Sharon O'Byrne, Meina T Tang
Etrolizumab, a humanized monoclonal antibody, specifically binds to the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. Pharmacokinetic (PK) and pharmacodynamic (PD) data were collected from an etrolizumab phase 1 trial in patients with moderate to severe ulcerative colitis (UC). We developed a mechanism-based model to simultaneously describe the kinetics of serum etrolizumab concentration and free β7 receptors on circulating intestinal-homing CD4+ T lymphocytes. Included in the analysis were 38 phase 1 UC patients who received single or 3 monthly doses of etrolizumab intravenously or subcutaneously across a dose range of 0...
November 26, 2017: Journal of Clinical Pharmacology
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