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https://www.readbyqxmd.com/read/28324749/a-phase-i-study-of-sar405838-a-novel-human-double-minute-2-hdm2-antagonist-in-patients-with-solid-tumours
#1
Maja de Jonge, Vincent A de Weger, Mark A Dickson, Marlies Langenberg, Axel Le Cesne, Andrew J Wagner, Karl Hsu, Wei Zheng, Sandrine Macé, Gilles Tuffal, Koruth Thomas, Jan H M Schellens
PURPOSE: In tumours with wild-type TP53, the tumour-suppressive function of p53 is frequently inhibited by HDM2. This phase I, dose-escalating study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and pharmacodynamics of SAR405838, an HDM2 inhibitor, in patients with advanced solid tumours (NCT01636479). METHODS: In dose escalation, patients with any locally advanced/metastatic solid tumour with TP53 mutation prevalence below 40%, or documented as TP53 wild-type, were eligible...
March 16, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28324691/comparison-of-three-different-types-of-cilostazol-loaded-solid-dispersion-physicochemical-characterization-and-pharmacokinetics-in-rats
#2
Omer Mustapha, Kyung Soo Kim, Shumaila Shafique, Dong Shik Kim, Sung Giu Jin, Youn Gee Seo, Yu Seok Youn, Kyung Taek Oh, Chul Soon Yong, Jong Oh Kim, Han-Gon Choi
The aim of this research was to compare three different types of cilostazol-loaded solid dispersion system including solvent-evaporated, solvent-wetted and surface-attached solid dispersion. The effect of polymers and surfactants on the aqueous solubility of cilostazol was investigated, leading to the selection of polyvinylpyrrolidone (PVP) and sodium lauryl sulphate (SLS). Employing a spray-drying technique, numerous surface-attached, solvent-evaporated and solvent-wetted solid dispersions were prepared with various amounts PVP and SLS using water, 90% ethanol and acetone, respectively...
March 9, 2017: Colloids and Surfaces. B, Biointerfaces
https://www.readbyqxmd.com/read/28324653/evaluation-of-brain-pharmacokinetic-and-neuropharmacodynamic-attributes-of-antiepileptic-drug-lacosamide-in-hepatic-and-renal-impairment-preclinical-evidence
#3
Baldeep Kumar, Manish Modi, Biman Saikia, Bikash Medhi
The knowledge of pharmacokinetic and pharmacodynamic properties of antiepileptic drugs is helpful in optimizing drug therapy for epilepsy. This study was designed to evaluate the pharmacokinetic and pharmacodynamic properties of lacosamide in experimentally induced hepatic and renal impairment in seizure animals. Hepatic or renal impairment was induced by injection of carbon tetrachloride or diclofenac sodium, respectively. After induction, the animals were administered with a single dose of lacosamide. At different time points, MES seizure recordings were done followed by isolation of plasma and brain samples for drug quantification and pharmacodynamic measurements...
March 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28324649/sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-pharmacokinetics-and-metabolic-properties-to-obtain-atropisomeric-quinolinone-am-0466-that-affords-robust-in-vivo-activity
#4
Russell F Graceffa, Alessandro A Boezio, Jessica Able, Steven Altmann, Loren M Berry, Christiane M Boezio, John R Butler, Margaret Y Chu-Moyer, Melanie Cooke, Erin F DiMauro, Thomas A Dineen, Elma Feric Bojic, Robert S Foti, Robert T Fremeau, Angel Guzman-Perez, Hua Gao, Hakan Gunaydin, Hongbing Huang, Liyue Huang, Christopher Ilch, Michael Jarosh, Thomas Kornecook, Charles R Kreiman, Daniel S La, Joseph Ligutti, Benjamin Charles Milgram, Min-Hwa Jasmine Lin, Isaac E Marx, Hanh Nho Nguyen, Emily A Peterson, Gwen Rescourio, John Roberts, Laurie B Schenkel, Roman Shimanovich, Brian Andrew Sparling, John Stellwagen, Kristin Taborn, Karina R Vaida, Jean Wang, John T S Yeoman, Violeta L Yu, Dawn Zhu, Bryan D Moyer, Matthew M Weiss
Due to its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a novel series of atropisomeric quinolinone sulfonamide inhibitors of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28324647/metabolism-and-distribution-of-clozapine-n-oxide-implications-for-nonhuman-primate-chemogenetics
#5
Jessica Raper, J Scott Daniels, Ryan D Morrison, Leonard Howell, Jocelyne Bachevalier, Thomas Wichmann, Adriana Galvan
The use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in neuroscience has rapidly expanded in rodent studies, but has lagged behind in nonhuman primate (NHP) experiments, slowing the development of this method for therapeutic use in humans. One reason for the slow adoption of DREADD technology in primates is that the pharmacokinetic properties and bioavailability of clozapine-n-oxide (CNO), the most commonly used ligand for human muscarinic (hM) DREADDs, are not fully described in primates...
March 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28324340/quantitative-18-f-fluorocholine-positron-emission-tomography-for-prostate-cancer-correlation-between-kinetic-parameters-and-gleason-scoring
#6
Joshua J D Schaefferkoetter, Ziting Wang, Mary C Stephenson, Sharmili Roy, Maurizio Conti, Lars Eriksson, David W Townsend, Thomas Thamboo, Edmund Chiong
BACKGROUND: The use of radiolabeled choline as a positron emission tomography (PET) agent for imaging primary tumors in the prostate has been evaluated extensively over the past two decades. There are, however, conflicting reports of its sensitivity and the relationship between choline PET imaging and disease staging is not fully understood. Moreover, relatively few studies have investigated the correlation between tracer uptake and histological tumor grade. This work quantified (18)F-fluorocholine in tumor and healthy prostate tissue using pharmacokinetic modeling and stratified uptake parameters by histology grade...
December 2017: EJNMMI Research
https://www.readbyqxmd.com/read/28324274/bioavailability-of-generic-0-05-difluprednate-emulsion-in-the-aqueous-humor-cornea-and-conjunctiva-of-new-zealand-rabbits-after-a-single-dose-compared-with-commercial-difluprednate
#7
Arieh Mercado-Sesma, Angélica Contreras-Rubio, Leopoldo Baiza-Durán, Oscar Olvera-Montaño, Mónica Miranda-Robles, José Bonilla-García
BACKGROUND: To determine the concentration after a single dose of generic 0.05% difluprednate and commercial difluprednate in the aqueous humor, cornea, and conjunctiva of New Zealand rabbits, a preclinical study in 72 male New Zealand white rabbits was performed. A single dose (50 μL) of two 0.05% difluprednate ophthalmic formulations was instilled in both eyes. Conjunctiva, cornea, and aqueous humor samples were collected at nine time points over 8 h (four animals per time point)...
December 2017: Journal of Ophthalmic Inflammation and Infection
https://www.readbyqxmd.com/read/28324011/a-novel-fc-fgf21-with-improved-resistance-to-proteolysis-increased-affinity-towards-%C3%AE-klotho-and-enhanced-efficacy-in-mice-and-cynomolgus-monkeys
#8
Shanaka Stanislaus, Randy Hecht, Junming Yie, Todd Hager, Michael Hall, Chris Spahr, Wei Wang, Jennifer Weiszmann, Yang Li, Liying Deng, Dwight Winters, Stephen Smith, Lei Zhou, Yuesheng Li, Murielle M Véniant, Jing Xu
FGF21 is a natural hormone that modulates glucose, lipid, and energy metabolism. Previously, we engineered an Fc fusion FGF21 variant with two mutations, Fc-FGF21(RG), to extend the half-life and reduce aggregation and in vivo degradation of FGF21. We now describe a new variant developed to reduce the extreme C-terminal degradation and improve the binding affinity to β-Klotho. We demonstrate, by introducing one additional mutation located at the C-terminus of FGF21 (A180E) that the new molecule, Fc-FGF21(RGE), has gained many improved attributes...
January 26, 2017: Endocrinology
https://www.readbyqxmd.com/read/28323948/dose-dependent-suppression-of-gonadotropins-and-ovarian-hormones-by-elagolix-in-healthy-premenopausal-women
#9
Juki Ng, Kristof Chwalisz, David C Carter, Cheri E Klein
Context: Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone dependent diseases in women. Objective: To evaluate the pharmacokinetics and pharmacodynamics of elagolix. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit. Interventions: Elagolix 150 mg once daily or 100, 200, 300 or 400 mg twice daily or placebo for 21 days...
February 16, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28319848/treatment-of-premenstrual-dysphoric-disorder-with-the-gabaa-receptor-modulating-steroid-antagonist-sepranolone-uc1010-a-randomized-controlled-trial
#10
Marie Bixo, Karin Ekberg, Inger Sundström Poromaa, Angelica Lindén Hirschberg, Aino Fianu Jonasson, Lotta Andréen, Erika Timby, Marianne Wulff, Agneta Ehrenborg, Torbjörn Bäckström
CONTEXT: Allopregnanolone is a metabolite from progesterone and a positive modulator of the GABAA receptor. This endogenous steroid may induce negative mood in sensitive women when present in serum levels comparable to the premenstrual phase. Its endogenous isomer, isoallopregnanolone, has been shown to antagonize allopregnanolone effects in experimental animal and human models. OBJECTIVE: The objective was to test whether inhibition of allopregnanolone by treatment with the GABAA modulating steroid antagonist (GAMSA) Sepranolone (UC1010) during the premenstrual phase could reduce symptoms of the premenstrual dysphoric disorder (PMDD)...
March 1, 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/28319829/evaluation-of-the-pharmacokinetics-of-imipenem-following-regional-limb-perfusion-using-the-saphenous-and-the-cephalic-veins-in-standing-horses
#11
G Kelmer, A J Tatz, E Kdoshim, M Britzi, G Segev
This prospective experimental study goal was to determine the pharmacokinetics of imipenem after intravenous regional limb perfusion (IV-RLP) in standing horses. Nine horses participated in the study; that was approved by the University Animal Care and Use Committee. One thoracic limb or one pelvic limb of each horse was randomly selected. After the veins were catheterized, an Esmarch bandage tourniquet was applied and the catheter was injected with a solution containing 500mg of imipenem. Synovial fluid samples were collected from the fetlock joint and blood samples were collected from the jugular vein...
February 24, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28319603/the-path-of-interchangeability-of-biosimilars-in-pediatric-inflammatory-bowel-disease-quality-before-cost-savings
#12
Dimple Patel, K T Park
The advent of biosimilars in inflammatory bowel disease (IBD) represents an opportunity for cost-savings and increased patient access to effective disease-modifying therapies. While preliminary data in adult IBD and rheumatology patients suggest comparable effectiveness and pharmacokinetics between original biologics and biosimilars, long-term immunogenicity data are unknown. Without this data, conclusions about interchangeability should not be made for pediatric patients with IBD. Children affected by IBD, in particular, are a vulnerable group if automatic substitution and non-medical switching are allowed based on limited data in adult patients...
March 17, 2017: Journal of Pediatric Gastroenterology and Nutrition
https://www.readbyqxmd.com/read/28318987/a-clinical-evaluation-of-the-pharmacokinetics-and-pharmacodynamics-of-intravenous-alfaxalone-in-cyclodextrin-in-male-and-female-rats-following-a-loading-dose-and-constant-rate-infusion
#13
Kate L White, Stuart Paine, John Harris
OBJECTIVE: To characterise, as a clinical study, the pharmacokinetics and pharmacodynamics and describe the hypnotic effect of the neurosteroid alfaxalone (3α-hydroxy-5 α-pregnane-11, 20-dione) formulated with 2-hydroxypropyl-β-cyclodextrin in male and female rats. STUDY DESIGN: Prospective, experimental laboratory study. ANIMALS: A total of 12 (six male and six female) adult, aged-matched Sprague Dawley rats. METHODS: Surgery and instrumentation was performed under isoflurane anaesthesia in an oxygen/nitrous oxide mixture (1:2) and local anaesthetic infiltration...
February 1, 2017: Veterinary Anaesthesia and Analgesia
https://www.readbyqxmd.com/read/28318747/ultra-fast-quantitation-of-voriconazole-in-human-plasma-by-coated-blade-spray-mass-spectrometry
#14
Marcos Tascon, Germán Augusto Gómez-Ríos, Nathaly Reyes-Garcés, Justen Poole, Ezel Boyacı, Janusz Pawliszyn
Voriconazole is a triazole broad-spectrum antifungal medication often used to treat fungal infections caused by Aspergillus and Fusarium species. One of the main challenges associated with the implementation of this medication is its narrow therapeutic concentration range, demonstrating toxicity at concentrations above 6μg/mL and limited efficacy at concentrations below 2μg/mL. As a result, methodologies which permit the rapid and accurate quantitation of voriconazole in patients are highly desirable. In this work two different approaches based on coated blade spray directly coupled to mass spectrometry (CBS-MS) are introduced; each enabling the quantitation of voriconazole in plasma samples with a simple and fast sample preparation and no chromatographic step...
March 12, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28318043/the-effects-of-pregnancy-on-the-pharmacokinetics-of-infliximab-and-adalimumab-in-inflammatory-bowel-disease
#15
C H Seow, Y Leung, N Vande Casteele, E Ehteshami Afshar, D Tanyingoh, G Bindra, M J Stewart, P L Beck, G G Kaplan, S Ghosh, R Panaccione
BACKGROUND: Transplacental transfer of infliximab and adalimumab results in detectable drug levels in the cord blood and infant. AIM: To determine if pregnancy influenced the pharmacokinetics of anti-TNF agents in women with inflammatory bowel disease. METHODS: Twenty-five women from the University of Calgary inflammatory bowel disease(IBD) pregnancy clinic on maintenance infliximab or adalimumab were recruited prospectively with serum bio-banking performed each trimester...
March 20, 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28317872/preclinical-evaluation-of-the-efficacy-pharmacokinetics-and-immunogenicity-of-js-001-a-programmed-cell-death-protein-1-pd-1-monoclonal-antibody
#16
Jie Fu, Fang Wang, Li-Hou Dong, Jing Zhang, Cheng-Lian Deng, Xue-Li Wang, Xin-Yao Xie, Jing Zhang, Ruo-Xian Deng, Li-Bo Zhang, Hai Wu, Hui Feng, Bo Chen, Hai-Feng Song
JS-001 is the first monoclonal antibody (mAb) against programmed cell death protein-1 (PD-1) approved by the China Food and Drug Administration (CFDA) into the clinical trails. To date, however, no pre-clinical pharmacological and pharmacokinetic (PK) data are available. In this study, we investigated the efficacy of JS-001 and conducted a preclinical PK study, including the monitoring of anti-drug antibodies (ADAs). We found that JS-001 specifically bound to PD-1 antigen with an EC50 of 21 nmol/L, and competently blocked the binding of PD-1 antigen to PD-L1 and PD-L2 with IC50 of 3...
March 20, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28317409/ombitasvir-and-paritaprevir-boosted-with-ritonavir-and-combined-with-dasabuvir-for-chronic-hepatitis-c
#17
Robert Flisiak, Marta Flisiak-Jackiewicz
Hepatitis C is a leading cause of cirrhosis and hepatocellular carcinoma responsible for almost 700,000 deaths worldwide annually. Until 2014, management of HCV infections was based on interferon alfa containing regimens, with efficacy of 40-70% and a high adverse event rate. Interferon-free therapeutic options improved sustained viral response (SVR) rate to >90% and safety profile to placebo-like levels. Areas covered: This article describes all-oral regimen consisting of three direct acting antivirals (DAA) - ombitasvir (OBV), paritaprevir (PTV) and dasabuvir (DSV), which in clinical practice is boosted with ritonavir (r) and sometimes with ribavirin (RBV)...
March 20, 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28317153/pharmacokinetics-and-pulmonary-distribution-of-gamithromycin-after-intravenous-administration-in-foals
#18
S Berlin, T Randow, E Scheuch, M Grube, M Venner, W Siegmund
The long-acting azalide antibiotic gamithromycin is marketed for intramuscular treatment of bovine and swine infections. Off-label use in foals leads to severe local lesions likely caused by hyperosmolality of the injected solution. We provide evidence from a pharmacokinetic study in 10 warm-blooded healthy foals for intravenous bolus injection of gamithromycin diluted in distilled water to be a safe and well tolerated alternative. By intravenous dosing, markedly higher plasma exposure and better penetration into bronchoalveolar lavage cells but lower distribution into epithelial lining fluid are achieved as after intramuscular or subcutaneous administration...
March 19, 2017: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28317144/uhplc-ms-ms-method-for-the-determination-of-omarigliptin-in-rat-plasma-and-its-application-to-a-pharmacokinetic-study-in-rats
#19
Meng-Fang Li, Xiao-Xia Hu, Ai-Qun Ma
Omarigliptin is a novel long-acting DPP-4 inhibitor used for the treatment of T2DM. In this work, a sensitive and selective UHPLC-MS/MS method was developed and validated for determination of omarigliptin in rat plasma. Sample preparation was performed by protein precipitation with acetonitrile. Chromatographic separation of analytes was achieved on a RRHD Eclipse Plus C18 column (2.1 × 50 mm, 1.8 µ), using gradient mobile phase (0.1% formic acid-acetonitrile) at a flow rate of 0.4 mL/min. Detection was performed in multiple reaction monitoring mode, with target fragment ions m/z 399...
March 19, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28317126/pharmacokinetics-of-ceftiofur-sodium-in-equine-pregnancy
#20
M L Macpherson, S Giguère, M A Pozor, E Runcan, T W Vickroy, S A Benson, M H T Troedsson, J N Hatzel, J Larson, E Vanden Berg, A A Kelleman, L C Sanchez, M M LeBlanc
Eleven pregnant pony mares (D270-326) were administered ceftiofur sodium intramuscularly at 2.2 mg/kg (n = 6) or 4.4 mg/kg (n = 5), once daily. Plasma was obtained prior to ceftiofur administration and at 0.5, 1, 2, 4, 8, 12, and 24 hr after administration. Eight pony mares were re-enrolled in the study at least 3 days from expected foaling to ensure steady-state concentrations of drug at the time of foaling. Mares were administered ceftiofur sodium (4.4 mg/kg, IM) daily until foaling. Parturition was induced using oxytocin 1 hr after ceftiofur sodium administration...
March 19, 2017: Journal of Veterinary Pharmacology and Therapeutics
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