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Pharmacokinetics pharmacodynamics

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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/28324653/evaluation-of-brain-pharmacokinetic-and-neuropharmacodynamic-attributes-of-antiepileptic-drug-lacosamide-in-hepatic-and-renal-impairment-preclinical-evidence
#2
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
#3
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/28324011/a-novel-fc-fgf21-with-improved-resistance-to-proteolysis-increased-affinity-towards-%C3%AE-klotho-and-enhanced-efficacy-in-mice-and-cynomolgus-monkeys
#4
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
#5
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/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
#6
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/28315259/scutellarin-protects-against-doxorubicin-induced-acute-cardiotoxicity-and-regulates-its-accumulation-in-the-heart
#7
Xi-Peng Sun, Li-Li Wan, Quan-Jun Yang, Yan Huo, Yong-Long Han, Cheng Guo
The clinical use of doxorubicin (DOX) is limited by its dose-dependent cardiotoxicity. The present study investigated the effects of scutellarin against DOX-induced cardiotoxicity in rats using pharmacodynamic and pharmacokinetic approaches. DOX (20 mg/kg) was injected intraperitoneally (i.p.) as a single dose, and scutellarin (5 mg/kg/day) was injected intravenously (i.v.) for 3 days. Rats treated with DOX showed acute cardiotoxicity as indicated by the elevated serum lactate dehydrogenase (LDH) activity (4057...
March 17, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28306152/assessment-of-ex-vivo-transport-function-in-isolated-rodent-brain-capillaries
#8
Gary N Y Chan, Ronald E Cannon
The blood-brain barrier plays an important role in neuroprotection; however, it can be a major obstacle for drug delivery to the brain. This barrier primarily resides in the brain capillaries and functions as an interface between the brain and peripheral blood circulation. Several anatomical and biochemical elements of the blood-brain barrier are essential to regulate the permeability of nutrients, ions, hormones, toxic metabolites, and xenobiotics into and out of the brain. In particular, high expression of ATP-driven efflux transporters at the blood-brain barrier is a major obstacle in the delivery of CNS pharmacotherapeutics to the brain...
March 17, 2017: Current Protocols in Pharmacology
https://www.readbyqxmd.com/read/28304215/use-of-statistical-and-pharmacokinetic-pharmacodynamic-modeling-and-simulation-to-improve-decision-making-a-section-summary-report-of-the-trends-and-innovations-in-clinical-trial-statistics-conference
#9
Holly Kimko, Seth Berry, Michael O'Kelly, Nitin Mehrotra, Matthew Hutmacher, Venkat Sethuraman
The application of modeling and simulation (M&S) methods to improve decision-making was discussed during the Trends & Innovations in Clinical Trial Statistics Conference held in Durham, North Carolina, USA on May 1-4, 2016. Uses of both pharmacometric and statistical M&S were presented during the conference, highlighting the diversity of the methods employed by pharmacometricians and statisticians to address a broad range of quantitative issues in drug development. Five presentations are summarized herein, which cover the development strategy of employing M&S to drive decision-making; European initiatives on best practice in M&S; case studies of pharmacokinetic/pharmacodynamics modeling in regulatory decisions; estimation of exposure-response relationships in the presence of confounding; and the utility of estimating the probability of a correct decision for dose selection when prior information is limited...
February 7, 2017: Journal of Biopharmaceutical Statistics
https://www.readbyqxmd.com/read/28303728/how-can-we-overcome-neuropsychological-adverse-effects-of-antiepileptic-drugs
#10
Juri-Alexander Witt, Christoph Helmstaedter
Antiepileptic pharmacotherapy can have a negative or positive impact on cognition and behavior. Besides individual susceptibilities (in terms of idiosyncratic reactions), the risk of adverse drug effects largely depends on treatment decisions. Therefore practical strategies to prevent neuropsychological side effects comprise (1.) selecting antiepileptic drugs (AEDs) with superior neuropsychological side effect profiles, (2.) restricting the individual drug load (target doses and number of concurrent AEDs), (3...
March 17, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28303726/pharmacokinetic-and-pharmacodynamic-variability-of-insulin-when-administered-by-jet-injection
#11
Elsemiek E C Engwerda, Cees J Tack, Bastiaan E de Galan
BACKGROUND: Jet injection has been shown to accelerate the absorption and action of rapid-acting insulin. In this study, we compared the variability of absorption characteristics between jet injection and conventional administration of the rapid-acting insulin analogue aspart. METHODS: A total of 30 healthy volunteers were enrolled in this randomized controlled blinded parallel study. On two test days, they received insulin aspart (0.2 units/kg body weight), either by jet injection or conventional pen, followed by a 6-hour euglycemic glucose clamp...
March 1, 2017: Journal of Diabetes Science and Technology
https://www.readbyqxmd.com/read/28303006/short-course-high-dose-rifampicin-achieves-wolbachia-depletion-predictive-of-curative-outcomes-in-preclinical-models-of-lymphatic-filariasis-and-onchocerciasis
#12
Ghaith Aljayyoussi, Hayley E Tyrer, Louise Ford, Hanna Sjoberg, Nicolas Pionnier, David Waterhouse, Jill Davies, Joanne Gamble, Haelly Metugene, Darren A N Cook, Andrew Steven, Raman Sharma, Ana F Guimaraes, Rachel H Clare, Andrew Cassidy, Kelly L Johnston, Laura Myhill, Laura Hayward, Samuel Wanji, Joseph D Turner, Mark J Taylor, Stephen A Ward
Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18-24 months post-treatment...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28300867/consistent-platelet-inhibition-with-ticagrelor-60-mg-twice-daily-following-myocardial-infarction-regardless-of-diabetes-status
#13
Mark R Thomas, Dominick J Angiolillo, Marc P Bonaca, Ramzi A Ajjan, Heather M Judge, Fabiana Rollini, Francesco Franchi, Arif J Ahsan, Deepak L Bhatt, Julia F Kuder, Philippe Gabriel Steg, Marc Cohen, Rangasamy Muthusamy, Marc S Sabatine, Robert F Storey
Diabetes increases cardiovascular risk and reduces pharmacodynamic response to some oral antiplatelet drugs. This study aimed to determine whether ticagrelor 60 mg twice daily (bid) provided potent and consistent platelet inhibition in patients with vs without diabetes in the PEGASUS-TIMI 54 platelet function substudy. Out of 180 patients studied, 58 patients were randomised to and had received at least four weeks of ticagrelor 60 mg bid, with 20 (34 %) having diabetes, 58 patients received ticagrelor 90 mg bid, with 12 (21 %) having diabetes, and 64 patients received placebo, with 18 (28 %) having diabetes...
March 16, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28296471/the-safety-of-multiple-flexible-sigmoidoscopies-with-mucosal-biopsies-in-healthy-clinical-trial-participants
#14
Wai Kan Chiu, Rhonda M Brand, Danielle Camp, Stacey Edick, Carol Mitchell, Sherri Karas, Amanda Zehmisch, Ken Ho, Randall E Brand, Janet Harrison, Steven Abo, Ross D Cranston, Ian McGowan
During Phase 1 pharmacokinetic/pharmacodynamics studies, participants may undergo multiple sigmoidoscopies, with a collection of 10-20 biopsies during each procedure. This article characterizes the safety of flexible sigmoidoscopies in clinical trial participants. We determined the number of flexible sigmoidoscopies and rectal biopsies that participants underwent and analyzed the frequency, duration, and severity of flexible sigmoidoscopy-related adverse events (AEs). During the study period, 278 participants underwent 1,004 flexible sigmoidoscopies with the collection of 15,930 rectal biopsies...
March 15, 2017: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/28296334/a-study-on-cyp2c19-and-cyp2d6-polymorphic-effects-on-pharmacokinetics-and-pharmacodynamics-of-amitriptyline-in-healthy-koreans
#15
S Ryu, S Park, J H Lee, Y R Kim, H S Na, H S Lim, H Y Choi, I Y Hwang, J G Lee, Z W Park, W Y Oh, J M Kim, S E Choi
We performed a double-blinded, genotype-based stratification study to explore the pharmacokinetics and pharmacodynamics of amitriptyline according to CYP2C19 and CYP2D6 genotype in Korean subjects. Twenty-four healthy adults were grouped by genotype of CYP2C19 and CYP2D6. After a single dose of 25 mg of amitriptyline, blood samples were collected and anticholinergic effects were measured. The extent of N-demethylation of amitriptyline significantly decreased in subjects carrying two nonfunctional alleles of CYP2C19...
March 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28295451/ccl20-neutralisation-by-a-monoclonal-antibody-in-healthy-subjects-selectively-inhibits-recruitment-of-ccr6-cells-in-an-experimental-suction-blister
#16
Gerben Bouma, Stefano Zamuner, Kirsty Hicks, Andrew Want, João Oliveira, Arpita Choudhury, Sara Brett, Darren Robertson, Leigh Felton, Virginia Norris, Disala Fernando, Michael Herdman, Ruth Tarzi
AIMS: GSK3050002, a humanized IgG1κ antibody with high binding affinity to human CCL20, was administered in a first-in-human study to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). An experimental skin suction blister model was employed to assess target engagement and the ability of the compound to inhibit recruitment of inflammatory CCR6 expressing cells. METHODS: This study was a randomized, double-blind (sponsor open), placebo-controlled, single-centre, single ascending intravenous dose escalation trial in 48 healthy male volunteers...
March 11, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28295239/eculizumab-dosing-regimen-in-atypical-hus-possibilities-for-individualized-treatment
#17
Elena Volokhina, Kioa Wijnsma, Renate van der Molen, Nel Roeleveld, Thea van der Velden, Joop Goertz, Fred Sweep, Roger J Brüggemann, Jack Wetzels, Nicole van de Kar, Lambertus van den Heuvel
Recent studies indicate that eculizumab is often given in excess to aHUS patients. Individualization of treatment is thus highly requested, however, data on pharmacokinetics and pharmacodynamics of eculizumab remain limited. We analyzed 11 patients during induction (weekly), maintenance (2-weekly) and tapering (every 3-8 weeks) phases of treatment. The trough eculizumab levels increased with each additional dose during the induction phase (depending on body weight). During maintenance, high eculizumab concentrations of up to 772 µg/mL were observed...
March 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28294526/phase-1-dose-escalating-study-of-the-safety-pharmacokinetics-and-pharmacodynamics-of-activated-factor-x-i-16l
#18
Dana Parsons-Rich, Fei Hua, Gang Li, Constantino Kantaridis, Debra D Pittman, Steven Arkin
BACKGROUND: FXa(I16L) (PF-05230907) is a zymogen-like variant of activated coagulation factor X (FXa). It exhibits enhanced resistance to inactivation by endogenous inhibitors compared with wild-type FXa and restores hemostatic activity in nonclinical models of various bleeding conditions. OBJECTIVES: To evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of FXa(I16L) , a phase 1, first-in-human, dose escalation clinical trial in healthy adult volunteers was conducted METHODS: Participants were assigned to 1 of 6 ascending single-dose cohorts (0...
March 14, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28294376/influence-of-the-pharmacokinetic-profile-on-the-plasma-glucose-lowering-effect-of-ppar%C3%AE-agonist-pioglitazone-in-wistar-fatty-rats
#19
Akihiko Goto, Yoshihiko Tagawa, Yoshiaki Kimura, Akifumi Kogame, Yuu Moriya, Nobuyuki Amano
Although the mechanism of action for peroxisome proliferator-activated receptor gamma (PPARγ) agonists has been extensively explored, the impact of the pharmacokinetic (PK) profile on the pharmacodynamic (PD) effects of PPARγ agonists has not been elucidated in detail. We evaluated the importance of the PK profile of PPARγ agonist for its PD effect based on population PK/PD analysis. Pioglitazone hydrochloride, the PPARγ agonist, was administered orally to Wistar fatty rats once a day (qd) or once every other day (q2d) as double the amount for the qd treatment...
March 11, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28294055/therapeutic-molecular-and-computational-aspects-of-novel-monoamine-oxidase-mao-inhibitors
#20
M Ramesh, Yussif M Dokurugu, Michael D Thompson, Mahmoud Soliman
Due to the limited number of MAOs inhibitors in the clinic and several research efforts are aimed at the discovery of novel MAOs inhibitors. At present, high specificity and a reversible mode of inhibition of MAO-A/B are cited as desirable traits in drug discovery process. This will help to reduce the probability of causing target disruption and may increase the duration of action. Most of the existing MAO inhibitors lead to side effects due to lack of affinity and selectivity. Therefore, there is an urgent need to design novel, potent, reversible and selective inhibitors for MAO-A/B...
March 10, 2017: Combinatorial Chemistry & High Throughput Screening
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