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https://www.readbyqxmd.com/read/28727908/leveraging-a-clinical-phase-ib-proof-of-concept-study-for-the-gpr40-agonist-mk-8666-in-patients-with-type-2-diabetes-for-model-informed-phase-ii-dose-selection
#1
A W Krug, P Vaddady, R A Railkar, B J Musser, J Cote, Agh Ederveen, D G Krefetz, E DeNoia, A L Free, L Morrow, M V Chakravarthy, E Kauh, D A Tatosian, P A Kothare
GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing...
July 20, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28727815/polymorphisms-associated-with-everolimus-pharmacokinetics-toxicity-and-survival-in-metastatic-breast-cancer
#2
Tomas Pascual, María Apellániz-Ruiz, Cristina Pernaut, Cecilia Cueto-Felgueroso, Pablo Villalba, Carlos Álvarez, Luis Manso, Lucia Inglada-Pérez, Mercedes Robledo, Cristina Rodríguez-Antona, Eva Ciruelos
PURPOSE: Metastatic breast cancer (MBC) progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS) compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs) on outcomes from this treatment through a pharmacogenetic analysis...
2017: PloS One
https://www.readbyqxmd.com/read/28726352/computational-design-of-a-specific-heavy-chain-%C3%AE%C2%BA-light-chain-interface-for-expressing-fully-igg-bispecific-antibodies
#3
K J Froning, A Leaver-Fay, X Wu, S Phan, L Gao, F Huang, A Pustilnik, M Bacica, K Houlihan, Q Chai, J R Fitchett, J Hendle, B Kuhlman, S J Demarest
The use of bispecific antibodies (BsAbs) to treat human diseases is on the rise. Increasingly complex and powerful therapeutic mechanisms made possible by BsAbs are being described in the literature and are spurring innovation of novel BsAb formats and methods for their production. The long-lived in vivo pharmacokinetics, optimal biophysical properties and potential effector functions of natural IgG monoclonal (and monospecific) antibodies has resulted in a push to generate fully IgG BsAb formats with the same quaternary structure as monoclonal IgGs...
July 20, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28726199/a-study-of-the-protective-properties-of-an-antibody-based-antidote-metabolizing-organophosphorus-pesticide-paraoxon
#4
Yu A Mokrushina, A V Stepanova, V A Palikov, A V Stepanov, G I Belous, I A Dyachenko, V D Knorre, I V Smirnov, A G Gabibov
A catalytic antibody A17 and its mutants highly efficiently interact with organophosphorus pesticide paraoxon. In this work, we studied the protective properties of antibody A17-K47 in paraoxon poisoning using a mouse model. The optimal paraoxon dose simulating the acute toxic effect of organophosphorus compounds was 550 μg/kg. The pharmacokinetic parameters of A17-K47 antibody were t1/2distr =7.2±1.4 min, t1/2el =330±20 min. The antibody did not cause toxic effects when administered at a ten-fold calculated therapeutic dose (610 mg/kg)...
July 18, 2017: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28726171/qsar-modeling-docking-and-admet-studies-for-exploration-of-potential-anti-malarial-compounds-against-plasmodium-falciparum
#5
Tabish Qidwai
Development of resistance in the Plasmodium falciparum to Artemisinin, the most effective anti-malarial compound, threatens malaria elimination tactics. To gain more efficacious Artemisinin derivatives, QSAR modeling and docking was performed. In the present study, 2D-QSAR model and molecular docking were used to evaluate the Artemisinin compounds and to reveal their binding modes and structural basis of inhibitory activity. Moreover, ADMET-related descriptors have been calculated to predict the pharmacokinetic properties of the effective compounds...
December 2016: In Silico Pharmacology
https://www.readbyqxmd.com/read/28726169/comparison-of-the-systemic-and-local-pharmacokinetics-of-clonidine-mucoadhesive-buccal-tablets-with-reference-clonidine-oral-tablets-in-healthy-volunteers-an-open-label-randomised-cross-over-trial
#6
Bérangère Vasseur, Alain Dufour, Laetitia Houdas, Helen Goodwin, Kathryn Harries, Neslihan Yesiltas Emul, Simon Hutchings
INTRODUCTION: The clonidine mucoadhesive buccal tablet (MBT) is a novel delivery system resulting in high and sustained concentrations of clonidine in the oral cavity. In a phase II clinical trial, clonidine MBT reduced the incidence of severe oral mucositis (OM) compared to placebo in head and neck cancer patients undergoing chemoradiation. This study compared the pharmacokinetics (PK), safety and tolerability of clonidine MBT with a reference oral tablet (OT). METHODS: This was a randomised, three-period, single-dose crossover study in 36 healthy subjects aged 18-50 years...
July 19, 2017: Advances in Therapy
https://www.readbyqxmd.com/read/28726132/phase-i-dose-escalation-study-of-nms-1286937-an-orally-available-polo-like-kinase-1-inhibitor-in-patients-with-advanced-or-metastatic-solid-tumors
#7
Glen J Weiss, Gayle Jameson, Daniel D Von Hoff, Barbara Valsasina, Cristina Davite, Claudia Di Giulio, Francesco Fiorentini, Rachele Alzani, Patrizia Carpinelli, Alessandro Di Sanzo, Arturo Galvani, Antonella Isacchi, Ramesh K Ramanathan
Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue...
July 20, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28726003/chitooligosaccharides-modified-reduction-sensitive-liposomes-enhanced-cytoplasmic-drug-delivery-and-osteosarcomas-tumor-inhibition-in-animal-models
#8
Xuelei Yin, Yingying Chi, Chuanyou Guo, Shuaishuai Feng, Jinhu Liu, Kaoxiang Sun, Zimei Wu
PURPOSE: To investigate the potential of a reduction-sensitive and fusogenic liposomes, enabled by surface-coating with chotooligosaccharides (COS) via a disulfide linker, for tumor-targeted cytoplasmic drug delivery. METHODS: COS (MW2000-5000) were chemically tethered onto the liposomes through a disulfide linker (-SS-) to cholesterol (Chol). Doxorubicin (DOX) was actively loaded in the liposomes. Their reduction-sensitivities, cellular uptake, cytotoxicity, pharmacokinetics and antitumor efficacy were investigated...
July 19, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28725140/formulation-and-pharmacokinetics-of-multi-layered-matrix-tablets-biphasic-delivery-of-diclofenac
#9
Ehab Mostafa Elzayat, Ali Abdelzaher Abdel-Rahman, Sayed Mohamed Ahmed, Fars Kaed Alanazi, Walid Abdulazim Habib, Hisham Suliman Abou-Auda, Adel Sakr
The rapid availability of the drug at the site of action followed by maintaining its effect for a long period of time is of great clinical importance. Thus, the purpose of the present study was to prepare and evaluate multi-layered matrix tablets of diclofenac using Eudragit RL/RS blend to achieve both immediate and sustained therapeutic effects. Diclofenac potassium (25 mg) was incorporated in an outer immediate release layer to provide immediate pain relief whereas diclofenac sodium (75 mg) was incorporated in the inner core to provide extended drug release...
July 2017: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
https://www.readbyqxmd.com/read/28725138/comparative-assessment-of-saliva-and-plasma-for-drug-bioavailability-and-bioequivalence-studies-in-humans
#10
Nasir M Idkaidek
Aims: To study the pharmacokinetics of selected drugs in plasma and saliva matrixes in healthy human volunteers, and to suggest using non-invasive saliva sampling instead of plasma as a surrogate in bioavailability and bioequivalence (BA/BE) studies. Methods: Four different pilot BA/BE studies were done in 12-18 healthy humans. Saliva and plasma samples were collected for 3-5 half life values of metformin, tolterodine, rosuvastatin, and paracetamol after oral dosing. Saliva and plasma samples were assayed using LC-MSMS, and then pharmacokinetic parameters were calculated by non-compartmental analysis using Kinetica program...
July 2017: Saudi Pharmaceutical Journal: SPJ: the Official Publication of the Saudi Pharmaceutical Society
https://www.readbyqxmd.com/read/28725042/global-deregulation-of-ginseng-products-may-be-a-safety-hazard-to-warfarin-takers-solid-evidence-of-ginseng-warfarin-interaction
#11
Haiyan Dong, Ji Ma, Tao Li, Yingying Xiao, Ning Zheng, Jian Liu, Yu Gao, Jingwei Shao, Lee Jia
Recent global deregulation of ginseng as the table food raises our concern about the possible ginseng-warfarin interaction that could be life-threatening to patients who take warfarin for preventing fatal strokes and thromboembolism while using ginseng products for bioenergy recovery. Here we show that quality-control ginsenosides, extracted from ginseng and containing its major active ingredients, produce dose- and time-dependent antagonism in rats against warfarin's anti-coagulation assessed by INR and rat thrombosis model...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28724692/enhancing-studies-of-pharmacodynamic-mechanisms-via-measurements-of-metabolic-flux
#12
Natalie A Daurio, Sheng-Ping Wang, Ying Chen, Haihong Zhou, David G McLaren, Thomas P Roddy, Douglas G Johns, Denise Milot, Takhar Kasumov, Mark D Erion, David E Kelley, Stephen F Previs
Drug discovery and development efforts are largely based around a common expectation, namely, direct or indirect action on a cellular process (e.g. statin-mediated enzyme inhibition or insulin-stimulated receptor activation) will have a beneficial impact on physiological homeostasis. To expand on this, one could argue that virtually all pharmacological interventions attempt to influence the flow of traffic in a biochemical network, irrespective of disease or modality. Since stable isotope tracer kinetic methods provide a measure of traffic flow (i...
July 19, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28724561/management-of-antithrombotic-agents-in-patients-undergoing-flexible-bronchoscopy
#13
REVIEW
Sami Abuqayyas, Shine Raju, John R Bartholomew, Roulan Abu Hweij, Atul C Mehta
Bleeding is one of the most feared complications of flexible bronchoscopy. Although infrequent, it can be catastrophic and result in fatal outcomes. Compared to other endoscopic procedures, the risk of morbidity and mortality from the bleeding is increased, as even a small amount of blood can fill the tracheobronchial tree and lead to respiratory failure. Patients using antithrombotic agents (ATAs) have higher bleeding risk. A thorough understanding of the different ATAs is critical to manage patients during the peri-procedural period...
September 30, 2017: European Respiratory Review: An Official Journal of the European Respiratory Society
https://www.readbyqxmd.com/read/28724555/susceptibility-testing-for-the-polymyxins-two-steps-back-three-steps-forward
#14
Shawn Vasoo
Optimizing and standardizing susceptibility testing for the polymyxins have become a pressing issue given the rise multidrug-resistant Gram-negative bacilli. Recently both CLSI-EUCAST have recommended broth microdilution (BMD) (without polysorbate) as the reference method for polymyxin susceptibility testing. In this issue, Chew et al. (doi: https://doi.org/10.1128JCM.00268-17.) compare the performance of three commercial BMD panels and the Etest to reference BMD for polymyxin B and colistin, on 76 Enterobacteriaceae isolates (21 mcr-1 positive)...
July 19, 2017: Journal of Clinical Microbiology
https://www.readbyqxmd.com/read/28724494/pharmacokinetics-of-a-novel-transdermal-fentanyl-solution-in-rhesus-macaques-macaca-mulatta
#15
Gregory W Salyards, Marie-Josee Lemoy, Heather K Knych, Ashley E Hill, Kari L Christe
Rhesus macaques (Macaca mulatta) are the most commonly used NHP biomedical model and experience both research and clinical procedures requiring analgesia. Opioids are a mainstay of analgesic therapy. A novel, transdermal fentanyl solution (TFS) has been developed as a long-acting, single-administration topical opioid and was reported to provide at least 4 d of effective plasma concentrations in beagles (Canis familiaris). To evaluate the pharmacokinetic profile of TFS in healthy adult rhesus macaques, we used a 2-period, 2-treatment crossover study of a single topical administration of 1...
July 1, 2017: Journal of the American Association for Laboratory Animal Science: JAALAS
https://www.readbyqxmd.com/read/28724261/development-of-a-sandwich-enzyme-linked-immunosorbent-assay-for-dtmp-gh-fusion-protein-by-rational-immunogen-selection
#16
Song Wang, Mingqiang Shen, Shilei Chen, Cheng Wang, Fang Chen, Mo Chen, Gaomei Zhao, Xinze Ran, Tianmin Cheng, Yongping Su, Yang Xu, Junping Wang
dTMP-GH is a chimeric protein containing a tandem dimer of thrombopoietin mimetic peptide (dTMP) fused to human growth hormone (hGH) prepared previously by our team. It shows significant bioactivity in promoting thrombocytopoiesis, but detection of intact dTMP-GH in plasma is still a challenge due to the presence of endogenous hGH. In this study, a rabbit polyclonal antibody with high affinity to dTMP was obtained with a BSA-conjugated immunogen composed of 20 amino acids sequence spanning two TMP and the linker...
December 2017: AMB Express
https://www.readbyqxmd.com/read/28724202/population-pharmacokinetics-of-lenalidomide-in-healthy-volunteers-and-patients-with-hematologic-malignancies
#17
Jamie N Connarn, Renfang Hwang, Yue Gao, Maria Palmisano, Nianhang Chen
A population pharmacokinetic (PopPK) model of lenalidomide was developed using data pooled from 13 clinical studies (dose range, 5-400 mg) in participants who were considered to have adequate capability for renal excretion of lenalidomide (creatinine clearance [CrCl] > 50 mL/min). The analysis population included 305 healthy volunteers and 83 patients with multiple myeloma or myelodysplastic syndromes. A 1-compartment model with linear absorption and elimination described well the observed data for both healthy volunteers and patients...
July 19, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28724181/finding-the-best-therapeutic-approach-for-pcos-the-importance-of-inositol-s-bioavailability
#18
B Orrù, R Circo, P Logoteta, S Petousis, G Carlomagno
Broadening clinical evidence has markedly designated inositol(s) as a common and effective therapeutic approach for PCOS and infertility. Although considerable research has been focused on the use in clinical practice of myo-inositol (myo-ins) and D-chiro-inositol (D-chiro-ins), the two major inositol stereoisomers, less attention has been paid to their bioavailability. Therefore, the aim of this paper is to gather and analyze information on inositol(s) bioavailability, to better delineate its optimal concentration for scientific and clinical purposes...
June 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28724168/efficacy-and-safety-of-glp-1-receptor-agonists-across-the-spectrum-of-type-2-diabetes-mellitus
#19
Lawrence A Leiter, Michael A Nauck
For patients with type 2 diabetes mellitus, glucagon-like peptide-1 receptor agonists (GLP-1RAs) generally exert robust glucose-lowering effects that are at least as effective as insulin. As monotherapies, changes from baseline in HbA1c with GLP-1RAs ranged from -1.9 to -0.7% in phase 3 trials. In addition, GLP-1RAs confer a low risk of hypoglycaemia and have a body-weight advantage (changes from baseline ranging from -4.0 to -0.4 kg). There is also evidence of significant reductions in risk for cardiovascular events with some of these agents, with a number of other trials underway...
July 2017: Experimental and Clinical Endocrinology & Diabetes
https://www.readbyqxmd.com/read/28724166/iron-pharmacokinetics-in-women-with-iron-deficiency-anaemia-following-a-single-oral-dose-of-a-novel-formulation-of-tardyferon-prolonged-release-ferrous-sulphate
#20
Andrew Leary, Laurence Barthe, Thierry Clavel, Claudie Sanchez, Zahida Issiakhem, Bruno Paillard, Jean-Marc Edmond
Numerous iron-containing preparations are available on the market; these vary in dosage, salt, chemical state of iron (ferric or ferrous) and in the iron delivery process (immediate or prolonged-release). Tardyferon® is a prolonged-release tablet containing 80 mg ferrous sulphate. The formulation has recently been modified; changes to the excipients which constitute the inert formulation matrix have allowed a decrease in tablet size for easier swallowing. The aim of this multicenter open-label study was to characterize the serum pharmacokinetics of iron in non-pregnant women aged 23-45 years with iron deficiency anaemia (IDA) following single oral administration of 160 mg Tardyferon® under fasting conditions...
July 19, 2017: Drug Research
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