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https://www.readbyqxmd.com/read/28661479/ochratoxin-a-induced-autophagy-in-vitro-and-in-vivo-promotes-porcine-circovirus-type-2-replication
#1
Gang Qian, Dandan Liu, Junfa Hu, Fang Gan, Lili Hou, Xingxiang Chen, Kehe Huang
Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium. Porcine circovirus type 2 (PCV2) is recognized as the causative agent of porcine circovirus-associated diseases. Recently, we reported that low doses of OTA promoted PCV2 replication in vitro and in vivo, but the underlying mechanism needed further investigation. The present studies further confirmed OTA-induced PCV2 replication promotion as measured by cap protein expression, viral titer, viral DNA copies and the number of infected cells...
June 29, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28439809/site-selection-a-case-study-in-the-identification-of-optimal-cysteine-engineered-antibody-drug-conjugates
#2
L Nathan Tumey, Fengping Li, Brian Rago, Xiaogang Han, Frank Loganzo, Sylvia Musto, Edmund I Graziani, Sujiet Puthenveetil, Jeffrey Casavant, Kimberly Marquette, Tracey Clark, Jack Bikker, Eric M Bennett, Frank Barletta, Nicole Piche-Nicholas, Amy Tam, Christopher J O'Donnell, Hans Peter Gerber, Lioudmila Tchistiakova
As the antibody drug conjugate (ADC) community continues to shift towards site-specific conjugation technology, there is a growing need to understand how the site of conjugation impacts the biophysical and biological properties of an ADC. In order to address this need, we prepared a carefully selected series of engineered cysteine ADCs and proceeded to systematically evaluate their potency, stability, and PK exposure. The site of conjugation did not have a significant influence on the thermal stability and in vitro cytotoxicity of the ADCs...
April 24, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28401480/target-mediated-drug-disposition-pharmacokinetic-pharmacodynamic-model-of-bosentan-and-endothelin-1
#3
Anke-Katrin Volz, Andreas Krause, Walter Emil Haefeli, Jasper Dingemanse, Thorsten Lehr
BACKGROUND AND OBJECTIVES: Bosentan is a competitive antagonist on endothelin receptor A and B (ETA and ETB), displacing the endogenous binding partner endothelin-1 (ET-1) from its binding sites. After administration of escalating single doses of 10-750 mg as an intravenous (i.v.) infusion, bosentan showed dose-dependent pharmacokinetics (PK). The aim of this analysis was to develop a PK model of bosentan after i.v. administration including competitive antagonism with ET-1 and to analyze its influence on blood pressure and heart rate with a combined pharmacokinetic/pharmacodynamic (PK/PD) model...
April 11, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28394888/amino-acid-composition-predicts-prion-activity
#4
Fayyaz Ul Amir Afsar Minhas, Eric D Ross, Asa Ben-Hur
Many prion-forming proteins contain glutamine/asparagine (Q/N) rich domains, and there are conflicting opinions as to the role of primary sequence in their conversion to the prion form: is this phenomenon driven primarily by amino acid composition, or, as a recent computational analysis suggested, dependent on the presence of short sequence elements with high amyloid-forming potential. The argument for the importance of short sequence elements hinged on the relatively-high accuracy obtained using a method that utilizes a collection of length-six sequence elements with known amyloid-forming potential...
April 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28207746/protease-resistance-of-infectious-prions-is-suppressed-by-removal-of-a-single-atom-in-the-cellular-prion-protein
#5
Henning Leske, Simone Hornemann, Uli Simon Herrmann, Caihong Zhu, Paolo Dametto, Bei Li, Florent Laferriere, Magdalini Polymenidou, Pawel Pelczar, Regina Rose Reimann, Petra Schwarz, Elisabeth Jane Rushing, Kurt Wüthrich, Adriano Aguzzi
Resistance to proteolytic digestion has long been considered a defining trait of prions in tissues of organisms suffering from transmissible spongiform encephalopathies. Detection of proteinase K-resistant prion protein (PrPSc) still represents the diagnostic gold standard for prion diseases in humans, sheep and cattle. However, it has become increasingly apparent that the accumulation of PrPSc does not always accompany prion infections: high titers of prion infectivity can be reached also in the absence of protease resistant PrPSc...
2017: PloS One
https://www.readbyqxmd.com/read/28146096/pharmacokinetics-studies-of-12-alkaloids-in-rat-plasma-after-oral-administration-of-zuojin-and-fan-zuojin-formulas
#6
Ping Qian, You-Bo Zhang, Yan-Fang Yang, Wei Xu, Xiu-Wei Yang
Zuojin formula (ZJ) is a traditional Chinese medicine (TCM) prescription consisted of Coptidis Rhizoma (CR) and Euodiae Fructus (EF), and has been used to treat gastrointestinal (GI) disease for more than 700 years. Fan-Zuojin formula (FZJ) is a related TCM prescription also consisted of CR and EF with the opposite proportion. In recent years, ZJ was getting more attention for its antitumor potential, but the indeterminate pharmacokinetic (PK) behavior restricted its clinical applications, and the PK differences between ZJ and FZJ were also largely unknown...
January 30, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27409329/reduced-oral-bioavailability-and-altered-pharmacokinetics-of-saquinavir-by-co-administration-with-biochanin-a-in-rats
#7
J Li, Y Liu, X Yu, J Zhang, J Gu, L Zhao
The study was aim to assess the impact of biochanin A on the oral bioavailability and pharmacokinetics (PK) of saquinavir (SQV), a substrate of P-glycoprotein (P-gp), in rats. 10 male rats were randomized into 2 groups of equal size, and administered orally 30 mg/kg SQV with or without 20 mg/kg biochanin A. The PK of SQV was assessed using non-compartmental analysis. Results revealed that the area under the plasma concentration-time curve of SQV from time zero to time infinity (AUC0-∞) was reduced by 51...
September 2016: Drug Research
https://www.readbyqxmd.com/read/27166489/-paradoxical-kinesia-in-parkinson-s-disease-theories-and-practical-application
#8
V V Cozac, L Rotaru
This literature review addresses the phenomenon of paradoxical kinesia (PK) in patients with Parkinson's disease (PD). PK is the sudden ability of the patient wit hPD to perform movements that were previously disturbed. This ability can be caused by different internal or environmental stressors. Different theories explaining the mechanism of paradoxical kinesia were proposed. In recent years, in the context of a search for new effective methods of treatment of akinesia I PD, methods of correction of motor impairment based on the phenomenon of PK are being developed...
2016: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
https://www.readbyqxmd.com/read/26697890/single-and-multiple-dose-pharmacokinetic-safety-and-tolerability-study-of-mildronate-injection-in-healthy-chinese-subjects-pharmacokinetic-of-mildronate-injection
#9
RANDOMIZED CONTROLLED TRIAL
Z Zhao, J Chen, W Peng, X Wang, Z Chen, H Tang, Y Liang, Z Ma, J Chen, X Chen, G Zhong, M Huang
Mildronate is an agent for cardioprotection and neuroprotection. This study aimed to evaluate the pharmacokinetic (PK) profiles, safety and tolerability of mildronate injection after single escalating doses and multiple doses in healthy Chinese subjects. We performed a randomized, open-label, single- and multiple-dose phase I trial including 3 doses of mildronate: 250, 500 and 750 mg. Plasma and urine samples were collected and concentrations of mildronate were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS)...
May 2016: Drug Research
https://www.readbyqxmd.com/read/26645096/optimizing-polymyxin-combinations-against-resistant-gram-negative-bacteria
#10
Phillip J Bergen, Zackery P Bulman, Cornelia B Landersdorfer, Nicholas Smith, Justin R Lenhard, Jürgen B Bulitta, Roger L Nation, Jian Li, Brian T Tsuji
Polymyxin combination therapy is increasingly used clinically. However, systematic investigations of such combinations are a relatively recent phenomenon. The emerging pharmacodynamic (PD) and pharmacokinetic (PK) data on CMS/colistin and polymyxin B suggest that caution is required with monotherapy. Given this situation, polymyxin combination therapy has been suggested as a possible way to increase bacterial killing and reduce the development of resistance. Considerable in vitro data have been generated in support of this view, particularly recent studies utilizing dynamic models...
December 2015: Infectious Diseases and Therapy
https://www.readbyqxmd.com/read/26639981/reduced-after-effects-following-podokinetic-adaptation-in-people-with-parkinson-s-disease-and-freezing-of-gait
#11
Samuel T Nemanich, Gammon M Earhart
INTRODUCTION: Gait dysfunction is common in people with Parkinson's disease (PD). Freezing of gait (FOG) is one such gait disturbance that significantly impacts mobility and quality of life in PD. Recent evidence suggests that cerebellar connectivity may differ in people with PD and FOG (PD+FOG) relative to those without FOG (PD-FOG). Investigation of gait adaptation, or the ability to change gait patterns in response to external perturbations, is cerebellum-dependent, is a practical means of probing cerebellar integrity and may provide additional insights regarding the FOG phenomenon...
January 2016: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/26387492/population-pharmacokinetics-of-rifampicin-in-chinese-patients-with-pulmonary-tuberculosis
#12
Ying Jing, Li Qin Zhu, Jian Wei Yang, Shu Ping Huang, Qian Wang, Jie Zhang
Rifampicin (RIF) induces cytochrome P450, which in turn catalyzes drug metabolism; however, pharmacokinetic studies on this phenomenon in the Chinese population, especially in the context of disease, are limited. Therefore, we sought to establish population-based pharmacokinetic models of RIF in a Chinese population with pulmonary tuberculosis (TB). Clinical data were retrospectively collected from 54 patients with pulmonary TB and analyzed alongside RIF blood levels from 95 samples collected prior to RIF administration and between 2 and 12 hours after treatment...
May 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/26341624/temporal-pharmacokinetic-pharmacodynamic-interaction-between-human-cd3%C3%AE%C2%B5-antigen-targeted-monoclonal-antibody-otelixizumab-and-cd3%C3%AE%C2%B5-binding-and-expression-in-human-peripheral-blood-mononuclear-cell-static-culture
#13
Kevin R Page, Enrica Mezzalana, Alexander J MacDonald, Stefano Zamuner, Giuseppe De Nicolao, Andre van Maurik
Otelixizumab is a monoclonal antibody (mAb) directed to human CD3ε, a protein forming part of the CD3/T-cell receptor (TCR) complex on T lymphocytes. This study investigated the temporal interaction between varying concentrations of otelixizumab, binding to human CD3 antigen, and expression of CD3/TCR complexes on lymphocytes in vitro, free from the confounding influence of changing lymphocyte frequencies observed in vivo. A static in vitro culture system was established in which primary human peripheral blood mononuclear cells (PBMCs) were incubated over an extended time course with titrated concentrations of otelixizumab...
November 2015: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/26247589/transgenic-mouse-bioassay-evidence-that-rabbits-are-susceptible-to-a-variety-of-prion-isolates
#14
Enric Vidal, Natalia Fernández-Borges, Belén Pintado, Hasier Eraña, Montserrat Ordóñez, Mercedes Márquez, Francesca Chianini, Dolors Fondevila, Manuel A Sánchez-Martín, Olivier Andreoletti, Mark P Dagleish, Martí Pumarola, Joaquín Castilla
Interspecies transmission of prions is a well-established phenomenon, both experimentally and under field conditions. Upon passage through new hosts, prion strains have proven their capacity to change their properties and this is a source of strain diversity which needs to be considered when assessing the potential risks associated with consumption of prion contaminated protein sources. Rabbits were considered for decades to be a prion resistant species until proven otherwise recently. To determine the extent of rabbit susceptibility to prions and to assess the effects of passage of different prion strains through this species a transgenic mouse model overexpressing rabbit PrPC was developed (TgRab)...
August 2015: PLoS Pathogens
https://www.readbyqxmd.com/read/26243731/label-free-kinetics-exploiting-functional-hemi-equilibrium-to-derive-rate-constants-for-muscarinic-receptor-antagonists
#15
Darren M Riddy, Celine Valant, Patricia Rueda, William N Charman, Patrick M Sexton, Roger J Summers, Arthur Christopoulos, Christopher J Langmead
Drug receptor kinetics is as a key component in drug discovery, development, and efficacy; however, determining kinetic parameters has historically required direct radiolabeling or competition with a labeled tracer. Here we present a simple approach to determining the kinetics of competitive antagonists of G protein-coupled receptors by exploiting the phenomenon of hemi-equilibrium, the state of partial re-equilibration of agonist, antagonist, and receptor in some functional assays. Using functional [Ca(2+)]i-flux and extracellular kinases 1 and 2 phosphorylation assays that have short incubation times and therefore are prone to hemi-equilibrium "behaviors," we investigated a wide range of structurally and physicochemically distinct muscarinic acetylcholine receptor antagonists...
October 2015: Molecular Pharmacology
https://www.readbyqxmd.com/read/26198698/haemophilus-parasuis-infection-activates-chemokine-rantes-in-pk-15-cells
#16
Yushan Chen, Shanshan Zhou, Kexin Hua, Hongde Xiao, Zili Li, Mei Liu, Rui Luo, Dingren Bi, Rui Zhou, Hui Jin
RANTES is a member of the CC chemokine involved in inflammation and immune response during pathogen infection. In our previous study, Haemophilus parasuis (H. parasuis), which is responsible for the great economic losses in the pig industry worldwide, has been shown to enhance RANTES expression in PK-15 cells. However, the mechanisms behind this biological phenomenon have remained unclear. In this study, we showed that H. parasuis infection significantly upregulated RANTES gene transcription in a time- and dose-dependent manner...
October 2015: Molecular Immunology
https://www.readbyqxmd.com/read/26028349/factors-influencing-inapplicability-of-cosolvency-induced-model-on-organic-acid-sorption-onto-humic-substance-from-methanol-mixture
#17
Minhee Kim, Juhee Kim, Jeong-Gyu Kim, Seunghun Hyun
Applicability of cosolvency model for describing the sorption of organic acids to humic substance was investigated by analyzing dataset of sorption (K m) and solubility (S m) of selected solutes (benzoic acid, 1-naphthoic acid, 2,4-dichlorophenoxyacetic acid, and 2,4,6-trichlorophenol (2,4,6-TCP)) as a function of pH(appCME) (apparent pH of liquid phase) and f c (methanol volume fractions). For all solutes, the K m decreased with f c with the K m reduction being less than the S m-based prediction. The slope of log K m-f c plot in the three organic carboxylic acids was well correlated with their cosolvency power, whereas the data of organic phenolic acid (2,4,6-TCP) was placed above the trend, indicating the different actions of functional groups...
October 2015: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/25730870/human-trypanolytic-factor-apol1-forms-ph-gated-cation-selective-channels-in-planar-lipid-bilayers-relevance-to-trypanosome-lysis
#18
Russell Thomson, Alan Finkelstein
Apolipoprotein L-1 (APOL1), the trypanolytic factor of human serum, can lyse several African trypanosome species including Trypanosoma brucei brucei, but not the human-infective pathogens T. brucei rhodesiense and T. brucei gambiense, which are resistant to lysis by human serum. Lysis follows the uptake of APOL1 into acidic endosomes and is apparently caused by colloid-osmotic swelling due to an increased ion permeability of the plasma membrane. Here we demonstrate that nanogram quantities of full-length recombinant APOL1 induce ideally cation-selective macroscopic conductances in planar lipid bilayers...
March 3, 2015: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/25334691/a-rare-case-of-adenocarcinoma-of-the-lung-harboring-egfr-braf-and-alk-activating-mutations
#19
Yang Yang, Xiao Song, Junjie Zhu, Xiao Zhou
Cancer Global Case ReportsSESSION TYPE: Global Case ReportPRESENTED ON: Tuesday, October 28, 2014 at 01:30 PM - 02:30 PMINTRODUCTION: Personalized target therapy of non-small cell lung cancer (NSCLC) is based on the mutation status of EGFR, KRAS, BRAF, and EML4-ALK fusion gene, and different mutations have different treatment. Herein, a rare case of adenocarcinoma of the lung harboring EGFR,BRAF and ALK activating mutations simultaneously was reported.CASE PRESENTATION: A 68-year-old male who is a light smoker (4 cigarettes per day) was admitted to our hospital in July 2013 because of chest distress and shortness of breath lasting > 2 years...
October 1, 2014: Chest
https://www.readbyqxmd.com/read/25185987/pharmacogenomics-in-the-intensive-care-unit-focus-on-potential-implications-for-clinical-practice
#20
REVIEW
John M Allen, Shyam Gelot
Critically ill patients often are at high-risk for adverse drug reactions (ADRs), mainly due to alterations in pharmacokinetic and pharmacodynamic (PK/PD) parameters. These PK/PD differences in can also lead to inadequate therapeutic response to many commonly used drugs in this patient population. Frequently in the critically ill patient, medications are utilized based on a "trial-and-error" approach. Furthermore, drug dosing in the critically ill largely remains a "one-size-fits-all" phenomenon, utilizing dosing based on PK studies in healthy volunteers...
2014: Recent Patents on Biotechnology
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