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Pharmacokinetics pharmacodynamics

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https://www.readbyqxmd.com/read/28231276/alterations-in-cellular-pharmacokinetics-and-pharmacodynamics-of-elvitegravir-in-response-to-ethanol-exposure-in-hiv-1-infected-monocytic-u1-cells
#1
Narasimha M Midde, Namita Sinha, Pradeep B Lukka, Bernd Meibohm, Santosh Kumar
Ethanol consumption is negatively associated with antiretroviral therapy (ART) adherence and general health in HIV positive individuals. Previously, we demonstrated ethanol-mediated alterations to metabolism of elvitegravir (EVG) in human liver microsomes. In the current study, we investigated ethanol influence on the pharmacokinetic and pharmacodynamic interactions of EVG in HIV infected monocytic (U1) cells. U1 cells were treated with 5 μM EVG, 2 μM Cobicistat (COBI), a booster drug, and 20 mM ethanol for up to 24 hours...
2017: PloS One
https://www.readbyqxmd.com/read/28230262/evaluation-of-the-immunogenicity-of-the-dabigatran-reversal-agent-idarucizumab-during-phase-i-studies
#2
Stephen Norris, Steven Ramael, Ippei Ikushima, Wouter Haazen, Akiko Harada, Viktoria Moschetti, Susumu Imazu, Paul A Reilly, Benjamin Lang, Joachim Stangier, Stephan Glund
AIMS: Idarucizumab, a humanized monoclonal anti-dabigatran antibody fragment, is effective in emergency reversal of dabigatran anticoagulation. Pre-existing and treatment-emergent anti-idarucizumab antibodies (antidrug antibodies; ADA) may affect the safety and efficacy of idarucizumab. This analysis characterized the pre-existing and treatment-emergent ADA and assessed their impact on the pharmacokinetics and pharmacodynamics (PK/PD) of idarucizumab. METHODS: Data were pooled from three phase I, randomized, double-blind idarucizumab studies in healthy Caucasian; elderly, renally impaired subjects; and healthy Japanese subjects...
February 23, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28229434/preclinical-pharmacokinetics-and-pharmacodynamics-of-pinometostat-epz-5676-a-first-in-class-small-molecule-s-adenosyl-methionine-competitive-inhibitor-of-dot1l
#3
Nigel J Waters
Acute leukemias bearing mixed lineage leukemia (MLL) rearrangements are aggressive diseases characterized by a poor overall prognosis despite multi-agent chemotherapy. Aberrant fusion proteins involving the MLL histone methyltransferase (HMT) lead to recruitment of DOT1L, to a multi-protein complex resulting in aberrant methylation of histone H3 lysine 79 at MLL target genes, and ultimately enhanced expression of critical genes for hematopoietic differentiation, including HOXA9 and MEIS1, and as such defines the established mechanism for leukemogenesis in MLL-rearrangement (MLL-r) leukemias...
February 22, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28226782/pharmacokinetic-and-pharmacodynamic-modeling-in-biogears
#4
Rachel B Clipp, Aaron Bray, Rodney Metoyer, M Cameron Thames, Jeffrey B Webb, Rachel B Clipp, Aaron Bray, Rodney Metoyer, M Cameron Thames, Jeffrey B Webb, M Cameron Thames, Rachel B Clipp, Jeffrey B Webb, Rodney Metoyer, Aaron Bray
Pharmacokinetics/pharmacodynamics models were designed and integrated into the BioGears® physiology engine to address the need for real time drug effects for varying patients and injury profiles. Ten drugs were validated using experimental and subject matter expert data. The plasma concentration curves had a good fit with experimental data and 48 of 50 physiologic parameters displayed a less than 10% error compared to the validation data.
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28226770/a-multiscale-model-based-analysis-of-the-multi-tissue-interplay-underlying-blood-glucose-regulation-in-type-i-diabetes
#5
Federico Wadehn, Stephan Schaller, Thomas Eissing, Markus Krauss, Lars Kupfer, Federico Wadehn, Stephan Schaller, Thomas Eissing, Markus Krauss, Lars Kupfer, Federico Wadehn, Markus Krauss, Lars Kupfer, Stephan Schaller, Thomas Eissing
A multiscale model for blood glucose regulation in diabetes type I patients is constructed by integrating detailed metabolic network models for fat, liver and muscle cells into a whole body physiologically-based pharmacokinetic/pharmacodynamic (pBPK/PD) model. The blood glucose regulation PBPK/PD model simulates the distribution and metabolization of glucose, insulin and glucagon on an organ and whole body level. The genome-scale metabolic networks in contrast describe intracellular reactions. The developed multiscale model is fitted to insulin, glucagon and glucose measurements of a 48h clinical trial featuring 6 subjects and is subsequently used to simulate (in silico) the influence of geneknockouts and drug-induced enzyme inhibitions on whole body blood glucose levels...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28226400/population-pharmacokinetics-and-pharmacodynamic-target-attainment-of-ampicillin-in-neonates-with-hypoxemic-ischemic-encephalopathy-in-the-setting-of-controlled-hypothermia
#6
Jeffrey J Cies, Keri N Fugarolas, Wayne S Moore, Robert W Mason, Ogechukwu R Menkiti
STUDY OBJECTIVE: To describe the population pharmacokinetics and pharmacodynamic target attainment of ampicillin in neonates with hypoxic-ischemic encephalopathy (HIE) undergoing controlled hypothermia (CH). DESIGN: Prospective, open-label pharmacokinetic study. SETTING: 189-bed, freestanding children's tertiary care teaching hospital. PATIENTS: Thirteen neonates (three females, 10 males) with HIE encephalopathy receiving CH and ampicillin 100 mg/kg/dose intravenously every 8 hours who were admitted to the neonatal intensive care unit between May 2013 and June 2014...
February 22, 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28224231/nc-6004-phase-i-study-in-combination-with-gemcitabine-for-advanced-solid-tumors-and-population-pk-pd-analysis
#7
Toshihiko Doi, Tetsuya Hamaguchi, Kohei Shitara, Satoru Iwasa, Yasuhiro Shimada, Mitsunori Harada, Kenichiro Naito, Naoto Hayashi, Atsuhiro Masada, Atsushi Ohtsu
OBJECTIVES: This study was an open-label phase I study to confirm the safety and tolerability of NC-6004 in combination with gemcitabine in Japanese patients with advanced solid tumors and to assess the PK effects of NC-6004 monotherapy. METHODS: This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) and recommended dose of NC-6004 combined with gemcitabine. Safety and pharmacokinetics were assessed. The administration of NC-6004 alone was started at 60 mg/m(2) every treatment cycle (21 days per cycle)...
February 21, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28223717/scale-up-and-pharmacokinetic-study-of-a-novel-mutated-chimeric-tissue-plasminogen-activator-mt-pa-in-rats
#8
Mozhgan Raigani, Mohammad-Reza Rouini, Ali-Akbar Golabchifar, Esmat Mirabzadeh, Behrouz Vaziri, Farzaneh Barkhordari, Fatemeh Davami, Fereidoun Mahboudi
Because of high mortality caused by cardiovascular diseases, various fibrinolytic agents with diverse pharmacokinetic and pharmacodynamic properties have been developed. A novel mutated chimeric tissue plasminogen activator (mt-PA) was developed by the removal of first three domains of t-PA, insertion of GHRP sequence and mutation towards resistance to plasminogen activator inhibitor-1 (PAI-1). Mt-PA protein was expressed in Expi293F cells. The expression level of mt-PA was found to be 5000 IU/mL. Following purification, the pharmacokinetic properties of mt-PA were evaluated in three doses in rats...
February 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28223378/population-pharmacokinetic-analysis-of-doripenem-after-intravenous-infusion-in-korean-patients-with-acute-infections
#9
Dong-Hwan Lee, Yong Kyun Kim, Kyubok Jin, Myoung Joo Kang, Young-Don Joo, Yang Wook Kim, Young Soo Moon, Jae-Gook Shin, Sungmin Kiem
We investigated population pharmacokinetics (PK) of doripenem in Korean patients with acute infections, and determined an appropriate dosing regimen using a Monte-Carlo simulation for predicting pharmacodynamics (PD). Patients (n = 37) with a creatinine clearance (CLCR) of 20∼50 mL/min or >50 mL/min who received a 250-mg or 500-mg dose of doripenem over the course of one hour every eight hours, respectively, were included in this study. Blood samples were taken pre-dose and 0 h, 0.5 h, and 4-6 h after the fourth infusion...
February 21, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28220483/pharmacokinetics-and-pharmacodynamics-of-metamizol-in-co-administration-with-morphine-under-acute-and-chronic-treatments-in-arthritic-rats
#10
Patricia Esmeralda Carrillo-Calzadilla, Francisco Javier López-Muñoz, Luis Alfonso Moreno-Rocha, José Raúl Medina-López, Alma Rosa Cortés-Arroyo, Adriana Miriam Domínguez-Ramírez
OBJECTIVE: To investigate the relationship between metamizol pharmacokinetics and the antinociceptive effect produced after subcutaneous administration of metamizol (177.8 mg/kg) alone or in combination with morphine (3.2 mg/kg), under acute and chronic treatments. METHODS: Antinociception was assessed using the pain-induced functional impairment model in rat (PIFIR). Serial blood samples were collected from the same animals to study the pharmacokinetics of metamizol...
February 21, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28219799/uplc-ms-ms-method-for-the-simultaneous-quantification-of-three-new-antiretroviral-drugs-dolutegravir-elvitegravir-and-rilpivirine-and-other-thirteen-antiretroviral-agents-plus-cobicistat-and-ritonavir-boosters-in-human-plasma
#11
Marco Simiele, Alessandra Ariaudo, Amedeo De Nicolò, Fabio Favata, Martina Ferrante, Chiara Carcieri, Stefano Bonora, Giovanni Di Perri, Antonio De Avolio
Rilpivirine (RPV), dolutegravir (DTG) and elvitegravir (EVG) are the latest antiretroviral drugs approved for treatment of HIV infection. Currently, poor information is currently available concerning their pharmacokinetic and pharmacodynamic properties, thus making the use of therapeutic drug monitoring for these drugs not useful. This lack of information is partially due to the absence of an high-throughput method for their simultaneous quantification together with other antiretroviral drugs. In this work, we describe the development and validation of a new UPLC-MS/MS method to quantify these drugs, together with other fourteen antiretroviral agents, in human plasma...
February 3, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28218410/pharmacokinetics-and-pharmacodynamics-of-tolvaptan-in-autosomal-dominant-polycystic-kidney-disease-phase-2-trials-for-dose-selection-in-the-pivotal-phase-3-trial
#12
Susan E Shoaf, Arlene B Chapman, Vicente E Torres, John Ouyang, Frank S Czerwiec
In the pivotal TEMPO 3:4 trial, the arginine vasopressin V2-receptor antagonist tolvaptan reduced the rate of kidney growth in patients with autosomal dominant polycystic kidney disease. Tolvaptan was initiated as daily morning/afternoon doses of 45/15 mg, and uptitrated weekly to 60/30 mg and 90/30 mg according to patient-reported tolerability. The current report describes 3 phase 2 trials in adult autosomal dominant polycystic kidney disease subjects that were the basis for the titrated split-dose regimen: a single ascending-dose trial (tolvaptan 15 to 120 mg; n = 11), a multiple split-dose trial (tolvaptan 15/15 mg, 30/0 mg, 30/15 mg, and 30/30 mg; n = 37), and an 8-week open-label safety and efficacy trial in 46 of the 48 subjects who participated in the prior 2 trials (tolvaptan 30/15 mg, 45/15 mg, 60/30 mg, and 90/30 mg)...
February 20, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28217868/an-anti-nicotinic-cognitive-challenge-model-using-mecamylamine-in-comparison-with-the-anti-muscarinic-cognitive-challenge-using-scopolamine
#13
A C Baakman, R Alvarez-Jimenez, R Rissmann, E S Klaassen, J Stevens, S C Goulooze, J Burger, E L Swart, J M A van Gerven, G J Groeneveld
INTRODUCTION: The muscarinic acetylcholine receptor antagonist scopolamine is often used for proof-of-pharmacology studies with pro-cognitive compounds. From a pharmacological point of view, it would seem more rational to use a nicotinic rather than a muscarinic anticholinergic challenge to prove pharmacology of a nicotinic acetylcholine receptor agonist. This study aims to characterize a nicotinic anticholinergic challenge model using mecamylamine and to compare it to the scopolamine model...
February 20, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28216902/feeble-antipyretic-analgesic-and-anti-inflammatory-activities-were-found-with-regular-dose-4-o-%C3%AE-d-glucosyl-5-o-methylvisamminol-one-of-the-conventional-marker-compounds-for-quality-evaluation-of-radix-saposhnikoviae
#14
Jing-Ming Yang, Hua Jiang, Hong-Liang Dai, Zi-Wei Wang, Gui-Zhi Jia, Xiang-Cai Meng
INTRODUCTION: 4'-O-β-D-glucosyl-5-O-methylvisamminol (GML) is a conventional marker compound for quality control of Radix Saposhnikoviae. Despite that, neither pharmacodynamic or pharmacokinetic information is available with regard to GML. As such, the aim of thisstudy was to assess the conventional evaluation indices for the quality of Radix Saposhnikoviae. MATERIALS AND METHODS: Pyretic animal model, hot plate test, and ear edema model were established to evaluate and compare the antipyretic, analgesic, and anti-inflammatory effect of the chromone derivativescimifugin, prime-O-glucosylcimifugin (PGCN), and GML in Radix Saposhnikoviae...
January 2017: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/28216475/the-effect-of-ticagrelor-administered-through-a-nasogastric-tube-to-comatose-patients-undergoing-acute-percutaneous-coronary-intervention-the-ticoma-study
#15
Hanna Ratcovich, Golnaz Sadjadieh, Hedvig B Andersson, Martin Frydland, Sebastian Wiberg, Nadia P Dridi, Jesper Kjaergaard, Lene Holmvang
AIMS: Patients in a coma after cardiac arrest may have adversely affected drug absorption and metabolism. This study, the first of its kind, aimed to investigate the early pharmacokinetic and pharmacodynamic effects of ticagrelor administered through a nasogastric tube (NGT) to patients resuscitated after an out of hospital cardiac arrest (OHCA) and undergoing primary percutaneous coronary intervention (pPCI). METHODS AND RESULTS: Blood samples were drawn at baseline and at two, four, six, eight, 12, and 24 hours and then daily for up to five days after administration of a 180 mg ticagrelor loading dose (LD), followed by 90 mg twice daily in 44 patients...
February 20, 2017: EuroIntervention
https://www.readbyqxmd.com/read/28213593/randomised-double-blind-parallel-group-placebo-controlled-study-to-evaluate-the-analgesic-efficacy-and-safety-of-vvz-149-injections-for-postoperative-pain-following-laparoscopic-colorectal-surgery
#16
Srdjan S Nedeljkovic, Darin J Correll, Xiaodong Bao, Natacha Zamor, Jose L Zeballos, Yi Zhang, Mark J Young, Johanna Ledley, Jessica Sorace, Kristen Eng, Carlyle P Hamsher, Rajivan Maniam, Jonathan W Chin, Becky Tsui, Sunyoung Cho, Doo H Lee
INTRODUCTION: In spite of advances in understanding and technology, postoperative pain remains poorly treated for a significant number of patients. In colorectal surgery, the need for developing novel analgesics is especially important. Patients after bowel surgery are assessed for rapid return of bowel function and opioids worsen ileus, nausea and constipation. We describe a prospective, double-blind, parallel group, placebo-controlled randomised controlled trial testing the hypothesis that a novel analgesic drug, VVZ -149, is safe and effective in improving pain compared with providing opioid analgesia alone among adults undergoing laparoscopic colorectal surgery...
February 17, 2017: BMJ Open
https://www.readbyqxmd.com/read/28213532/susceptibility-and-pk-pd-relationships-of-staphylococcus-aureus-strains-from-ovine-and-caprine-with-clinical-mastitis-against-five-veterinary-fluoroquinolones
#17
J M Serrano-Rodríguez, C Cárceles-García, C M Cárceles-Rodríguez, M L Gabarda, J M Serrano-Caballero, E Fernández-Varón
Minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of veterinary fluoroquinolones as enrofloxacin, its metabolite ciprofloxacin, danofloxacin, difloxacin and marbofloxacin against Staphylococcus aureus strains (n=24) isolated from milk of sheep and goats affected by clinical mastitis were evaluated. The authors have used the MIC and MPC, as well as the pharmacokinetic-pharmacodynamic relationships in plasma and milk. MIC values were significantly different between drugs, unlike MPC values...
February 17, 2017: Veterinary Record
https://www.readbyqxmd.com/read/28213092/prediction-of-thyroid-c-cell-carcinogenicity-after-chronic-administration-of-glp1-r-agonists-in-rodents
#18
Willem van den Brink, Annette Emerenciana, Francesco Bellanti, Oscar Della Pasqua, Jan Willem van der Laan
Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products...
February 16, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28213088/personalized-medicine-genetic-risk-prediction-of-drug-response
#19
REVIEW
Ge Zhang, Daniel W Nebert
Pharmacogenomics (PGx), a substantial component of "personalized medicine", seeks to understand each individual's genetic composition to optimize drug therapy -- maximizing beneficial drug response, while minimizing adverse drug reactions (ADRs). Drug responses are highly variable because innumerable factors contribute to ultimate phenotypic outcomes. Recent genome-wide PGx studies have provided some insight into genetic basis of variability in drug response. These can be grouped into three categories. [a] Monogenic (Mendelian) traits include early examples mostly of inherited disorders, and some severe (idiosyncratic) ADRs typically influenced by single rare coding variants...
February 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28211169/a-first-in-human-study-of-ds-1040-an-inhibitor-of-the-activated-form-of-thrombin-activatable-fibrinolysis-inhibitor-in-healthy-subjects
#20
Jin Zhou, Jarema Kochan, Ophelia Yin, Vance Warren, Cynthia Zamora, George Atiee, Joseph Pav, Yasushi Orihashi, Vijay Vashi, Victor Dishy
BACKGROUND: Current treatments for acute ischemic stroke and venous thromboembolism, such as recombinant tissue plasminogen activator and thrombectomy, are limited by a narrow time window and the risk of bleeding. DS-1040 is a novel low-molecular weight compound inhibiting the activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa), developed as a fibrinolysis enhancer for treatment of thromboembolic diseases. OBJECTIVES: This first-in-human, randomized, placebo-controlled, three-part, phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DS-1040 in healthy subjects...
February 17, 2017: Journal of Thrombosis and Haemostasis: JTH
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