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https://www.readbyqxmd.com/read/29353350/clinical-pharmacokinetics-and-pharmacodynamics-of-evolocumab-a-pcsk9-inhibitor
#1
REVIEW
Sreeneeranj Kasichayanula, Anita Grover, Maurice G Emery, Megan A Gibbs, Ransi Somaratne, Scott M Wasserman, John P Gibbs
Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein cholesterol (LDL-C) by decreasing expression of the LDL receptor on hepatic cells. Evolocumab is a human monoclonal immunoglobulin G2 that binds specifically to human PCSK9 to reduce LDL-C. Evolocumab exhibits nonlinear kinetics as a result of binding to PCSK9. Elimination is predominantly through saturable binding to PCSK9 at lower concentrations and a nonsaturable proteolytic pathway at higher concentrations. The effective half-life of evolocumab is 11-17 days...
January 20, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29352469/amoxicillin-current-use-in-swine-medicine
#2
REVIEW
D G S Burch, D Sperling
Amoxicillin has become a major antimicrobial substance in pig medicine for the treatment and control of severe, systemic infections such as Streptococcus suis. The minimum inhibitory concentration 90% (MIC 90) is 0.06 μg amoxicillin/ml, and the proposed epidemiological cut-off value (ECOFF) is 0.5 μg/ml, giving only 0.7% of isolates above the ECOFF or of reduced susceptibility. Clinical breakpoints have not been set for amoxicillin against porcine pathogens yet, hence the use of ECOFFs. It has also been successfully used for bacterial respiratory infections caused by Actinobacillus pleuropneumoniae and Pasteurella multocida...
January 19, 2018: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29351372/a-preclinical-population-pharmacokinetic-model-for-anti-cd20-cd3-t-cell-dependent-bispecific-antibodies
#3
Gregory Z Ferl, Arthur Reyes, Liping L Sun, Melissa Cheu, Amy Oldendorp, Saroja Ramanujan, Eric G Stefanich
CD20 is a cell-surface receptor expressed by healthy and neoplastic B cells and is a well-established target for biologics used to treat B-cell malignancies. Pharmacokinetic (PK) and pharmacodynamic (PD) data for the anti-CD20/CD3 T-cell-dependent bispecific antibody BTCT4465A were collected in transgenic mouse and nonhuman primate (NHP) studies. Pronounced nonlinearity in drug elimination was observed in the murine studies, and time-varying, nonlinear PK was observed in NHPs, where three empirical drug elimination terms were identified using a mixed-effects modeling approach: i) a constant nonsaturable linear clearance term (7 mL/day/kg); ii) a rapidly decaying time-varying, linear clearance term (t½  = 1...
January 19, 2018: Clinical and Translational Science
https://www.readbyqxmd.com/read/29350568/abp-980-promising-trastuzumab-biosimilar-for-her2-positive-breast-cancer
#4
Elisavet Paplomata, Rita Nahta
Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies. Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016-2017 ASCO and ESMO conference proceedings for "ABP 980" or "trastuzumab biosimilar"...
January 19, 2018: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29348926/a-double-blind-placebo-controlled-single-ascending-dose-study-of-remyelinating-antibody-rhigm22-in-people-with-multiple-sclerosis
#5
Andrew Eisen, Benjamin M Greenberg, James D Bowen, Douglas L Arnold, Anthony O Caggiano
Objective: The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22). Methods: Seventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months...
October 2017: Multiple Sclerosis Journal—Experimental, Translational and Clinical
https://www.readbyqxmd.com/read/29348681/impact-of-a-five-dimensional-framework-on-r-d-productivity-at-astrazeneca
#6
REVIEW
Paul Morgan, Dean G Brown, Simon Lennard, Mark J Anderton, J Carl Barrett, Ulf Eriksson, Mark Fidock, Bengt Hamrén, Anthony Johnson, Ruth E March, James Matcham, Jerome Mettetal, David J Nicholls, Stefan Platz, Steve Rees, Michael A Snowden, Menelas N Pangalos
In 2011, AstraZeneca embarked on a major revision of its research and development (R&D) strategy with the aim of improving R&D productivity, which was below industry averages in 2005-2010. A cornerstone of the revised strategy was to focus decision-making on five technical determinants (the right target, right tissue, right safety, right patient and right commercial potential). In this article, we describe the progress made using this '5R framework' in the hope that our experience could be useful to other companies tackling R&D productivity issues...
January 19, 2018: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29346838/first-in-human-study-to-assess-safety-pharmacokinetics-and-pharmacodynamics-of-bms-962212-a-direct-reversible-small-molecule-factor-xia-inhibitor-in-non-japanese-and-japanese-healthy-subjects
#7
Vidya Perera, Joseph M Luettgen, Zhaoqing Wang, Charles E Frost, Cynthia Yones, Cesare Russo, John Lee, Yue Zhao, Frank P LaCreta, Xuewen Ma, Robert M Knabb, Dietmar Seiffert, Mary DeSouza, Pierre Mugnier, Brenda Cirincione, Takayo Ueno, Robert J A Frost
AIMS: To assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class Factor XIa inhibitor, in Japanese and non-Japanese healthy subjects. METHODS: This was a randomized, placebo-controlled, double-blind, sequential, ascending dose study of 2 hour (Part A) and 5 day (Part B) intravenous (IV) infusions of BMS-962212. Part A used 4 doses (1.5, 4, 10, and 25 mg h-1 ) assigned to BMS-962212 or placebo in a 3:1 ratio per dose. Part B used 4 doses (1, 3, 9, and 20 mg h-1 ) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese subjects (n = 4 active, n = 1 placebo) per dose...
January 18, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29346833/phase-1b-trial-of-ficlatuzumab-a-humanized-hepatocyte-growth-factor-inhibitory-monoclonal-antibody-in-combination-with-gefitinib-in-asian-patients-with-nsclc
#8
Eng-Huat Tan, Wan-Teck Lim, Myung-Ju Ahn, Quan-Sing Ng, Jin Seok Ahn, Daniel Shao-Weng Tan, Jong-Mu Sun, May Han, Francis C Payumo, Krista McKee, Wei Yin, Marc Credi, Shefali Agarwal, Jaroslaw Jac, Keunchil Park
Hepatocyte growth factor (HGF)/c-Met pathway dysregulation is a mechanism for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Ficlatuzumab (AV-299; SCH 900105), a humanized IgG1 κ HGF inhibitory monoclonal antibody, prevents HGF/c-Met pathway ligand-mediated activation. This phase 1b study assessed the safety/tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of ficlatuzumab plus gefitinib in Asian patients with previously treated advanced non-small cell lung cancer (NSCLC)...
January 18, 2018: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/29345594/should-stemi-patients-receive-opiate-analgesia-the-morphine-paradox
#9
Mohamed Farag, Nikolaos Spinthakis, Manivannan Srinivasan, Diana Adrienne Gorog
BACKGROUND: The very significant benefit of P2Y12 receptor inhibitor administration in patients with ST-elevation myocardial infarction (STEMI), in reducing future ischaemic events and stent thrombosis, is undisputed. Morphine analgesia is very frequently co-administered to these patients for pain relief, along with antiplatelet therapy, at the time of presentation, and prior to reperfusion with primary percutaneous coronary intervention. METHODS: Research and online content related to opiates use in STEMI was reviewed...
January 17, 2018: Current Vascular Pharmacology
https://www.readbyqxmd.com/read/29345591/should-antithrombotic-treatment-strategies-in-east-asians-differ-from-caucasians-focused-on-acs-or-pci-treated-patients
#10
Jae Seok Bae, Jong-Hwa Ahn, Udaya Tantry, Paul A Gurbel, Young-Hoon Jeong
With over 1.5 billion people, East Asians are the most populous race in the world. Health status in this population is an important global issue. In the contemporary trials of antithrombotic treatment, East Asian patients have a lower risk for atherothrombotic diseases (especially, coronary artery disease [CAD]) and a higher risk for bleeding (especially, gastrointestinal bleeding and hemorrhagic stroke). Despite these observations, antithrombotic treatment strategies in East Asian patients are mainly based on the American or European guidelines that are derived from randomized, controlled trials including mostly Caucasians...
January 16, 2018: Current Vascular Pharmacology
https://www.readbyqxmd.com/read/29343524/antitumor-properties-of-raf709-a-highly-selective-and-potent-inhibitor-of-raf-kinase-dimers-in-tumors-driven-by-mutant-ras-or-braf
#11
Wenlin Shao, Yuji Mishina, Yun Feng, Giordano Caponigro, Vesselina G Cooke, Stacy Rivera, Yingyun Wang, Fang Shen, Joshua M Korn, Lesley Mathews Griner, Gisele Nishiguchi, Alice Rico, John Tellew, Jacob Haling, Robert Aversa, Valery R Polyakov, Richard Zang, Mohammad Hekmat-Nejad, Payman Amiri, Mallika Singh, Nicholas Keen, Michael P Dillon, Emma Lees, Savithri Ramurthy, William R Sellers, Darrin D Stuart
Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF...
January 17, 2018: Cancer Research
https://www.readbyqxmd.com/read/29342199/a-non-linear-pharmacokinetic-pharmacodynamic-relationship-of-metformin-in-healthy-volunteers-an-open-label-parallel-group-randomized-clinical-study
#12
Hyewon Chung, Jaeseong Oh, Seo Hyun Yoon, Kyung-Sang Yu, Joo-Youn Cho, Jae-Yong Chung
BACKGROUND: The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers. METHODS: A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration...
2018: PloS One
https://www.readbyqxmd.com/read/29341245/pharmacokinetic-pharmacodynamic-drug-drug-interactions-of-avatrombopag-when-co-administered-with-dual-or-selective-cyp2c9-and-cyp3a-interacting-drugs
#13
Maiko Nomoto, Cynthia A Zamora, Edgar Schuck, Peter Boyd, Min-Kun Chang, Jagadeesh Aluri, Y Amy Siu, W George Lai, Sanae Yasuda, Jim Ferry, Bhaskar Rege
AIMS: Avatrombopag, a thrombopoietin receptor agonist, is a substrate of cytochrome P450 (CYP) 2C9 and CYP3A. We assessed three drug-drug interactions of avatrombopag as a victim with dual or selective CYP2C9/3A inhibitors and inducers. METHODS: This was a 3-part, open-label study. Forty-eight healthy subjects received single 20 mg doses of avatrombopag alone or with one of 3 CYP2C9/3A inhibitors or inducers: fluconazole 400 mg once daily for 16 days, itraconazole 200 mg twice daily on Day 1 and 200 mg once daily on Days 2-16, or rifampin 600 mg once daily for 16 days...
January 16, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29341179/better-characterization-of-vinflunine-pharmacokinetics-variability-and-exposure-toxicity-relationship-to-improve-its-use-analyses-from-18-trials
#14
A Schmitt, L Nguyen, G Zorza, P Ferré, A Pétain
AIMS: Vinflunine is a novel tubulin-targeted inhibitor indicated as a single agent for the treatment of bladder cancers after failure of prior platinum-based therapy. Its pharmacokinetics (PK) and pharmacodynamics (PD) have been independently characterized through several phase I and phase II studies. However, no global pharmacometric analysis had been conducted yet. METHODS: Vinflunine concentrations and safety data from 18 phase I and phase II studies were used to conduct population PK and PK/PD analysis, using Nonmem...
January 17, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29340539/the-spectrum-of-cardiovascular-effects-of-dobutamine-from-healthy-subjects-to-septic-shock-patients
#15
Arnaldo Dubin, Bernardo Lattanzio, Luis Gatti
Dobutamine is the inotrope most commonly used in septic shock patients to increase cardiac output and correct hypoperfusion. Although some experimental and clinical studies have shown that dobutamine can improve systemic and regional hemodynamics, other research has found that its effects are heterogenous and unpredictable. In this review, we analyze the pharmacodynamic properties of dobutamine and its physiologic effects. Our goal is to show that the effects of dobutamine might differ between healthy subjects, in experimental and clinical cardiac failure, in animal models and in patients with septic shock...
October 2017: Revista Brasileira de Terapia Intensiva
https://www.readbyqxmd.com/read/29339551/inhibition-of-flt3-and-pim-kinases-by-ec-70124-exerts-potent-activity-in-preclinical-models-of-acute-myeloid-leukemia
#16
Noelia Puente-Moncada, Paula Costales, Isaac Antolín, Luz Elena Núñez, Patricia Oro, Maria Ana Hermosilla, Jhudit Perez-Escuredo, Nicolas Rios-Lombardia, Ana M Sanchez-Sanchez, Elisa Luño, Carmen Rodriguez, Vanesa Martin, Francisco Moris
Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myeloid leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations...
January 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29339394/population-pharmacokinetics-of-finafloxacin-in-healthy-volunteers-and-patients-with-complicated-urinary-tract-infections
#17
Max Taubert, Mark Lückermann, Andreas Vente, Axel Dalhoff, Uwe Fuhr
Background: Finafloxacin is a novel fluoroquinolone with increased antibacterial activity at acidic pH and reduced susceptibility to several resistance mechanisms. A phase II study revealed a good efficacy/safety profile in patients with complicated urinary tract infections (cUTI) while pharmacokinetics was characterized by highly variable concentration vs. time profiles, suggesting the need for an elaborated pharmacokinetic model.Methods: Data from three clinical trials were evaluated; 127 healthy volunteers were dosed orally (N=77) or intravenously (N=50) and 139 patients with cUTI received finafloxacin intravenously...
January 16, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29339392/a-novel-piperazine-based-drug-lead-for-cryptosporidiosis-from-the-medicines-for-malaria-venture-open-access-malaria-box
#18
R S Jumani, K Bessoff, M S Love, P Miller, E E Stebbins, J E Teixeira, M A Campbell, M J Meyers, J A Zambriski, V Nunez, A K Woods, C W McNamara, C D Huston
Cryptosporidiosis causes life-threatening diarrhea in children under age five, and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to a need for new drugs, better knowledge of drug properties that drive in vivo efficacy is needed to facilitate drug development. We report identification of a piperazine-based lead compound for Cryptosporidium drug development, MMV665917, and a new pharmacodynamic method used for its characterization...
January 16, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29339228/stability-and-plasmatic-protein-binding-of-novel-zidovudine-prodrugs-targeting-site-ii-of-human-serum-albumin
#19
Esteban M Schenfeld, Sergio R Ribone, Mario A Quevedo
Despite its vastly demonstrated clinical efficacy, zidovudine (AZT) exhibits several suboptimal pharmacokinetic properties. In particular, its short plasmatic half-life (t1/2 ~ 1 h) is related to its low bound fraction to whole plasmatic proteins and in particular to human serum albumin (HSA). The design of prodrugs constitutes a promising strategy to enhance AZT pharmacokinetic properties, including its affinity for HSA. Recently, we reported the synthesis and chemical stability evaluation of three novel prodrugs of AZT obtained by derivatization with dicarboxylic acids (1-3)...
January 12, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29338667/docosahexaenoic-acid-prevents-resistance-to-antiepileptic-drugs-in-two-animal-models-of-drug-resistant-epilepsy
#20
Melika Moezifar, Mohammad Sayyah, Morteza Zendehdel, Hakimeh Gavzan
OBJECTIVES: One-third of epileptic patients are resistant to antiepileptic drugs. Few clinical studies with small sample size indicate that polyunsaturated fatty acids could control drug-resistant epilepsy. We examined the efficacy of acute and chronic administration of docosahexaenoic acid (DHA) in two animal models of drug-resistant epilepsies, i.e. 6-Hz psychomotor seizures in mice and lamotrigine (LTG)-resistant kindled rats. METHODS: Mice received a single injection of DHA (300 µM, i...
January 16, 2018: Nutritional Neuroscience
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