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https://www.readbyqxmd.com/read/28723729/wnt-signaling-in-cardiovascular-disease-opportunities-and-challenges
#1
Austin Gay, Dwight A Towler
PURPOSE OF REVIEW: Cardiometabolic diseases increasingly afflict our aging, dysmetabolic population. Complex signals regulating low-density lipoprotein receptor-related protein (LRP) and frizzled protein family members - the plasma membrane receptors for the cadre of Wnt polypeptide morphogens - contribute to the control of cardiovascular homeostasis. RECENT FINDINGS: Both canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) Wnt signaling programs control vascular smooth muscle (VSM) cell phenotypic modulation in cardiometabolic disease...
July 18, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28721753/nintedanib-in-ovarian-cancer
#2
Saira Khalique, Susana Banerjee
Advanced ovarian cancer remains an unmet clinical need. Angiogenesis is considered a therapeutic target in ovarian cancer, with bevacizumab, a monoclonal antibody against VEGF, being the first drug to show a progression-free survival benefit. Nintedanib is an oral tyrosine kinase inhibitor targeting VEGF receptor 1-3, FGFR 1-3 and PDGFR α and β, which has entered phase III trial development in ovarian cancer. Areas covered: This article reviews the preclinical and clinical efficacy of nintedanib in ovarian cancer, its pharmacokinetic and pharmacodynamics profile, safety issues, together with an overview of clinical trials carried out so far...
July 19, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28721081/insulin-glargine-300-u-ml-for-basal-insulin-therapy-in-type-1-and-type-2-diabetes-mellitus
#3
REVIEW
Ip Tim Lau, Ka Fai Lee, Wing Yee So, Kathryn Tan, Vincent Tok Fai Yeung
OBJECTIVE: To review published clinical studies on the efficacy and safety of new insulin glargine 300 units/mL (Gla-300), a new long-acting insulin analog, for the treatment of type 1 and type 2 diabetes mellitus (T1DM, T2DM). MATERIALS AND METHODS: Data sources comprised primary research articles on Gla-300, including pharmacodynamic, pharmacokinetic, and clinical studies. RESULTS: In pharmacodynamic and pharmacokinetic studies, Gla-300 showed a flatter time-action profile and longer duration of action than Gla-100...
2017: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
https://www.readbyqxmd.com/read/28721067/phase-i-dose-escalation-study-of-long-acting-pasireotide-in-patients-with-neuroendocrine-tumors
#4
James C Yao, Jennifer A Chan, Alain C Mita, Madan G Kundu, Karina Hermosillo Reséndiz, Ke Hu, Shoba Ravichandran, Jonathan R Strosberg, Edward M Wolin
This phase I study aimed at determining the maximum tolerated dose (MTD) and characterizing the safety, tolerability, pharmacokinetics (PKs), and efficacy of pasireotide in patients with advanced neuroendocrine tumors (NETs). Patients were enrolled in two phases: dose-escalation phase (to determine the MTD) at a starting dose of 80 mg pasireotide long-acting release (LAR) i.m. followed by a dose-expansion phase (to evaluate safety and prelimi-nary efficacy). Associations between PK/pharmacodynamic parameters and clinical outcomes were evaluated using linear regression analysis...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28721014/determining-optimal-dosing-regimen-of-oral-administration-of-dicloxacillin-using-monte-carlo-simulation
#5
Wei Yu, Jinru Ji, Tingting Xiao, Chaoqun Ying, Jiaheng Fang, Ping Shen, Yonghong Xiao
BACKGROUND: Dicloxacillin, a semisynthetic isoxazolyl penicillin, exhibits antimicrobial activity against a wide variety of Gram-positive bacteria, as well as stability against penicillinases and low level of toxicity. The objective of this study was to obtain optimal dosing regimen of oral administration of dicloxacillin by analyzing the pharmacokinetic (PK) index in healthy volunteers and in vitro antibacterial activity by using Monte Carlo simulation. MATERIALS AND METHODS: A total of 867 clinical isolates from community-onset infections were collected from 31 secondary hospitals in People's Republic of China...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28720897/a-predictive-mathematical-modeling-approach-for-the-study-of-doxorubicin-treatment-in-triple-negative-breast-cancer
#6
Matthew T McKenna, Jared A Weis, Stephanie L Barnes, Darren R Tyson, Michael I Miga, Vito Quaranta, Thomas E Yankeelov
Doxorubicin forms the basis of chemotherapy regimens for several malignancies, including triple negative breast cancer (TNBC). Here, we present a coupled experimental/modeling approach to establish an in vitro pharmacokinetic/pharmacodynamic model to describe how the concentration and duration of doxorubicin therapy shape subsequent cell population dynamics. This work features a series of longitudinal fluorescence microscopy experiments that characterize (1) doxorubicin uptake dynamics in a panel of TNBC cell lines, and (2) cell population response to doxorubicin over 30 days...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28720398/perinatal-and-neonatal-use-of-paracetamol-for-pain-relief
#7
REVIEW
Karel Allegaert, John N van den Anker
Paracetamol (acetaminophen) is the most widely used drug to treat pain or fever in pregnant women or neonates, but its pharmacokinetics (PK) and pharmacodynamics (PD) warrant a focused analysis. During pregnancy, there is an important increase in paracetamol clearance. Consequently, it is reasonable to anticipate that the analgesic effect of paracetamol will decrease faster, whereas higher doses may result in even higher oxidative toxic metabolites. Therefore, most peripartal PD data relate to multimodal analgesia strategies...
July 15, 2017: Seminars in Fetal & Neonatal Medicine
https://www.readbyqxmd.com/read/28720346/pharmacokinetic-data-reduce-uncertainty-in-the-acceptable-daily-intake-for-benzoic-acid-and-its-salts
#8
K Zu, D M Pizzurro, T A Lewandowski, J E Goodman
The current acceptable daily intake (ADI) for benzoic acid and its salts as food additives is 0-5 mg/kg bw-day. This accounts for a total uncertainty factor (UF) of 100, which includes a default factor of 10 for interspecies differences. Based on pharmacokinetic data in rodents and humans, we derived a chemical-specific adjustment factor (CSAF) of 2 for the pharmacokinetic component of the interspecies UF. Additional analyses indicate that this CSAF is conservative and interspecies differences between rats and humans are likely closer to unity...
July 15, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/28719359/levodopa-in-parkinson-s-disease-a-review-of-population-pharmacokinetics-pharmacodynamics-analysis
#9
Amélie Marsot, Romain Guilhaumou, Jean Philippe Azulay, Olivier Blin
BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Although levodopa remains the single effective agent in the management of Parkinson's disease, the accurate determination of this optimal dosage is complicated by marked between-subject and between-occasion variability in this population.  This review presents a synthesis of the population pharmacokinetic and pharmacodynamic models of levodopa described in Parkinson's disease...
2017: Journal of Pharmacy & Pharmaceutical Sciences: a Publication of the Canadian Society for Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28719152/a-first-in-human-phase-i-multicenter-open-label-dose-escalation-study-of-the-oral-raf-vegfr-2-inhibitor-raf265-in-locally-advanced-or-metastatic-melanoma-independent-from-braf-mutation-status
#10
Benjamin Izar, William Sharfman, F Stephen Hodi, Donald Lawrence, Keith T Flaherty, Ravi Amaravadi, Kevin B Kim, Igor Puzanov, Jeffrey Sosman, Reinhard Dummer, Simone M Goldinger, Lyhping Lam, Shefali Kakar, Zhongwen Tang, Oliver Krieter, David F McDermott, Michael B Atkins
To establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, and anti-tumor efficacy of RAF265. We conducted a multicenter, open-label, phase-I, dose-escalation trial of RAF265, an orally available RAF kinase/VEGFR-2 inhibitor, in patients with advanced or metastatic melanoma. Pharmacokinetic (PK) analysis, pharmacodynamics (PD) and tumor response assessment were conducted. We evaluated metabolic tumor response by 18[F]-fluorodeoxyglucose-positron-emission tomography (FDG-PET), tissue biomarkers using immunohistochemistry (IHC), and modulators of angiogenesis...
July 18, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28716651/significance-of-a-to-i-rna-editing-of-transcripts-modulating-pharmacokinetics-and-pharmacodynamics
#11
REVIEW
Masataka Nakano, Miki Nakajima
RNA editing is a post-transcriptional process that alters the nucleotide sequence of RNA transcripts to generate transcriptome diversity. Among the various types of RNA editing, adenosine-to-inosine (A-to-I) RNA editing is the most frequent type of RNA editing in mammals. Adenosine deaminases acting on RNA (ADAR) enzymes, ADAR1 and ADAR2, convert adenosines in double-stranded RNA structures into inosines by hydrolytic deamination. Inosine forms a base pair with cytidine as if it were guanosine; therefore, the conversion may affect the amino acid sequence, splicing, microRNA targeting, and miRNA maturation...
July 14, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28715978/the-role-of-efflux-pumps-in-tuberculosis-treatment-and-their-promise-as-a-target-in-drug-development-unraveling-the-black-box
#12
Lindsey H M Te Brake, Gerjo J de Knegt, Jurriaan E de Steenwinkel, Teunis J P van Dam, David M Burger, Frans G M Russel, Reinout van Crevel, Jan B Koenderink, Rob E Aarnoutse
Insight into drug transport mechanisms is highly relevant to the efficacious treatment of tuberculosis (TB). Major problems in TB treatment are related to the transport of antituberculosis (anti-TB) drugs across human and mycobacterial membranes, affecting the concentrations of these drugs systemically and locally. Firstly, transporters located in the intestines, liver, and kidneys all determine the pharmacokinetics and pharmacodynamics of anti-TB drugs, with a high risk of drug-drug interactions in the setting of concurrent use of antimycobacterial, antiretroviral, and antidiabetic agents...
July 17, 2017: Annual Review of Pharmacology and Toxicology
https://www.readbyqxmd.com/read/28714411/pharmacology-and-literature-review-based-on-related-death-and-non-fatal-case-reports-of-the-benzofurans-and-benzodifurans-designer-drugs
#13
Bernardino Barceló Martín, Isabel Gomila
BACKGROUND: Benzofurans and benzodifurans are two groups of psychoactive substances that had originally been synthesized for research purpose. Benzofurans' structure is quite similar to the known recreational drug 3,4-methylenedioxymethamphetamine together with its active metabolite 3,4-methylenedioxyamphetamine. Benzodifurans are closely related to phenethylamines, but have more hallucinogens effects and much longer duration of action. This study aims to review the accessible evidence-based literature on benzofurans and benzodifurans pharmacology and toxicology...
July 14, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28714394/nanoparticle-mediated-delivery-of-neuroprotective-substances-for-the-treatment-of-diabetic-retinopathy
#14
Rosario Amato, Massimo Dal Monte, Matteo Lulli, Vittoria Raffa, Giovanni Casini
Diabetic retinopathy (DR) is a major complication of diabetes, characterized by extensive vascular pathology leading to vision loss. Neuronal suffering and death are also present in the diabetic retina as a result of different molecular mechanisms that are compromised or modified in response to high glucose and that mainly include excitotoxicity, advanced glycation, inflammation and oxidative stress. Recent data indicate that the vascular changes may be secondary to damage of retinal neurons and that neurodegeneration is likely to play a primary role in the development of DR...
July 17, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/28712941/rituximab-biosimilar-and-reference-rituximab-in-patients-with-previously-untreated-advanced-follicular-lymphoma-assist-fl-primary-results-from-a-confirmatory-phase-3-double-blind-randomised-controlled-study
#15
Wojciech Jurczak, Ilídia Moreira, Govind Babu Kanakasetty, Eduardo Munhoz, Maria Asunción Echeveste, Pratyush Giri, Nelson Castro, Juliana Pereira, Luiza Akria, Sergey Alexeev, Eugeniy Osmanov, Peijuan Zhu, Siyka Alexandrova, Angela Zubel, Olof Harlin, Jutta Amersdorffer
BACKGROUND: GP2013 is a rituximab biosimilar developed to stringent development guidelines, including non-clinical and preclinical investigations and clinical trials in rheumatoid arthritis and follicular lymphoma. We aimed to compare the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of GP2013 plus cyclophosphamide, vincristine, and prednisone (GP2013-CVP) with rituximab-CVP (R-CVP) in patients with follicular lymphoma. METHODS: In this phase 3, multinational, double-blind, randomised, controlled trial, adults (aged 18 years or older) with previously untreated, advanced stage (Ann Arbor stage III or IV) follicular lymphoma of WHO histological grades 1, 2, or 3a were randomly assigned (1:1) using interactive response technology to eight cycles of GP2013-CVP or R-CVP (combination phase), followed by monotherapy maintenance in responders for a 2-year period...
July 13, 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28710878/6-mercaptopurine-modifies-cerebrospinal-fluid-t-cell-abnormalities-in-pediatric-opsoclonus-myoclonus-as-steroid-sparer
#16
Michael R Pranzatelli, Elizabeth D Tate, Tyler J Allison
The purpose was to evaluate the capacity of 6-mercaptopurine (6-MP), a known immunosuppressant, to normalize cerebrospinal fluid (CSF) lymphocyte frequencies in opsoclonus-myoclonus syndrome (OMS) and function as a steroid sparer. CSF and blood lymphocytes were immunophenotyped in 11 children with OMS (without CSF B cell expansion), using a comprehensive panel of cell surface adhesion, activation, and maturation markers by flow cytometry, and referenced to 18 pediatric controls. Drug metabolites, lymphocyte counts, and liver function tests were used clinically to monitoring therapeutic range and toxicity...
July 15, 2017: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/28709989/evaluating-biapenem-dosage-regimens-in-intensive-care-unit-patients-with-pseudomonas-aeruginosa-infections-a-pharmacokinetic-pharmacodynamic-analysis-using-monte-carlo-simulation
#17
Yongfu Hang, Yafang Chen, Ling Xue, Shusen Sun, Long Liu, Jie Gao, Cheng Xie, Xianfeng Zhang, Jianguo Zhu, Jun Jin, Liyan Miao
This study sought to both identify optimal dosage regimens and estimate pharmacokinetic/pharmacodynamics characteristics of short-infusion (SI) versus extended-infusion (EI) for the use of biapenem against Pseudomonas aeruginosa infections in Chinese Intensive Care patients. A total of 85 strains of P. aeruginosa were collected, and the minimum inhibitory concentration (MIC) of biapenem was measured by the serial two-fold agar dilution method. We designed four frequently used clinical regimens: biapenem 300mg I...
July 11, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28708227/a-correlation-study-of-fluorouracil-pharmacodynamics-with-clinical-efficacy-and-toxicity
#18
Ece Esin, Tugba Akin Telli, Deniz Yuce, Suayib Yalcin
PURPOSE: Plasma 5-fluorouracil (5-FU) concentrations vary greatly between individuals who have received standard dosage. Pharmacokinetic adjusted doses have been hypothesized to overcome the possibility of potential toxicity and ineffectiveness related to inappropriate plasma levels of 5-FU. In this study, we prospectively investigated the clinical benefit and toxicity of 5-FU in relation to its pharmacokinetic properties. METHODS: Pharmacokinetics, effectiveness, and toxicity of 5-FU were investigated in 101 patients...
July 8, 2017: Tumori
https://www.readbyqxmd.com/read/28707591/new-generation-non-ssri-antidepressants-therapeutic-drug-monitoring-and-pharmacological
#19
Roberto Mandrioli, Michele Protti, Laura Mercolini
BACKGROUND: New-generation antidepressants (NGAs) are the latest additions to the clinician's arsenal in the fight against depression. After the introduction of selective serotonin reuptake inhibitors (SSRIs), a plethora of other groups followed, identified by their main mechanisms of activity: serotonin and norepinephrine reuptake inhibitors (SNRI); serotonin modulators and stimulators (SMS); serotonin antagonists and reuptake inhibitors (SARI); noradrenergic and selective serotonergic antidepressants (NaSSA); norepinephrine reuptake inhibitors (NeRI); serotonin, norepinephrine and dopamine reuptake inhibitors (SNDRI) or triple reuptake inhibitors (TRI); and melatonin and serotonin agonists (MaSA)...
July 12, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28706488/postnatal-maturation-of-the-glomerular-filtration-rate-in-conventional-growing-piglets-as-potential-juvenile-animal-model-for-preclinical-pharmaceutical-research
#20
Elke Gasthuys, Mathias Devreese, Joske Millecam, Stanislas Sys, Katrien Vanderperren, Joris Delanghe, Johan Vande Walle, Marjolein Heyndrickx, Siska Croubels
Adequate animal models are required to study the preclinical pharmacokinetics (PK), pharmacodynamics (PD) and safety of drugs in the pediatric subpopulation. Over the years, pigs were presented as a potential animal model, since they display a high degree of anatomical and physiological similarities with humans. To assess the suitability of piglets as a preclinical animal model for children, the ontogeny and maturation processes of several organ systems have to be unraveled and compared between both species...
2017: Frontiers in Pharmacology
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