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https://www.readbyqxmd.com/read/28637023/cationic-liquid-crystalline-nanoparticles-for-the-delivery-of-synthetic-rnai-based-therapeutics
#1
Emanuela Gentile, Taro Oba, Jing Lin, Ruping Shao, Feng Meng, Xiaobo Cao, Heather Y Lin, Majidi Mourad, Apar Pataer, Veerabhadran Baladandayuthapani, Dong Cai, Jack A Roth, Lin Ji
RNA interference (RNAi)-based therapeutics have been used to silence the expression of targeted pathological genes. Small interfering RNA (siRNAs) and microRNA (miRNAs) inhibitor have performed this function. However, short half-life, poor cellular uptake, and nonspecific distribution of small RNAs call for the development of novel delivery systems to facilitate the use of RNAi. We developed a novel cationic liquid crystalline nanoparticle (CLCN) to efficiently deliver synthetic siRNAs and miRNAs. CLCNs were prepared by using high-speed homogenization and assembled with synthetic siRNA or miRNA molecules in nuclease-free water to create CLCN/siRNA or miRNA complexes...
June 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636806/ph-dependent-general-base-catalyzed-activation-rather-than-isocyanate-liberation-may-explain-the-superior-anticancer-efficacy-of-laromustine-compared-to-related-1-2-bis-methylsulfonyl-1-2-chloroethyl-hydrazine-prodrugs
#2
P G Penketh, R A Finch, R Sauro, R P Baumann, E S Ratner, K Shyam
Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short-lived chloroethylating agent with anticancer activity. The short half-life of 90CE necessitates the use of latentiated prodrug forms for in vivo treatments. Alkylaminocarbonyl based prodrugs such as laromustine exhibit significantly superior in vivo activity in several murine tumor models compared to analogs utilizing acyl, and alkoxycarbonyl latentiating groups. The alkylaminocarbonyl prodrugs possess two exclusive characteristics: (i) they are primarily unmasked by spontaneous base catalyzed elimination; and (ii) they liberate a reactive carbamoylating species...
June 21, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28636348/the-development-of-an-aryloxazole-class-of-hepatitis-c-virus-inhibitors-targeting-the-entry-stage-of-the-viral-replication-cycle
#3
Shanshan He, Kelin Li, Billy Lin, Zonyi Hu, Jingbo Xiao, Xin Hu, Amy Q Wang, Xin Xu, Marc Ferrer, Noel Southall, Wei Zheng, Jeffrey Aubé, Frank J Schoenen, Juan J Marugan, T Jake Liang, Kevin J Frankowski
Reliance on hepatitis C virus (HCV) replicon systems and protein-based screening assays has led to treatments that target HCV viral replication proteins. The model does not encompass other viral replication cycle steps, such as entry, processing, assembly and secretion, or viral host factors. We previously applied a phenotypic high-throughput screening platform based on an infectious HCV system and discovered an aryloxazole-based anti-HCV hit. Structure-activity relationship studies revealed several compounds exhibiting EC50 values below 100 nM...
June 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28636208/a-phase-i-trial-of-prn1008-a-novel-reversible-covalent-inhibitor-of-bruton-s-tyrosine-kinase-in-healthy-volunteers
#4
Patrick F Smith, Janakan Krishnarajah, Philip A Nunn, Ron J Hill, Dane Karr, D Tam, Mohammad Masjedizadeh, Jens O Funk, Steve G Gourlay
AIM: To evaluate the safety, tolerability, and PK/PD of PRN1008, a novel BTK inhibitor, in healthy volunteers, and thus determine the dose range for future clinical studies. METHODS: This was a two-part randomized, placebo controlled study in healthy volunteers using a liquid formulation. Part I was a single ascending dose design with dose levels of 50 to 1200 mg (n=6 active, 2 placebo per cohort); Part II was a multiple ascending dose design, with dose regimens ranging from 300 mg to 900 mg daily, either qd or bd for 10 days...
June 21, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28634686/respiratory-uptake-and-depuration-kinetics-of-perfluorooctanesulfonate-pfos-in-a-marine-sandworm-species
#5
Takeo Sakurai, Jun Kobayashi, Nozomi Ito, Shigeko Serizawa, Hiroaki Shiraishi, Tohru Yabe, Yuichi Ishii, Noriyuki Suzuki
We determined the respiratory uptake and depuration kinetics of perfluorooctanesulfonate (PFOS) in Perinereis wilsoni, a polychaete sandworm used as a model species to investigate the fate of chemical pollutants in coastal environments. The sandworms were kept in gravel-packed containers, and the water levels were varied cyclically to mimic the tides. We used seawater kept at 17.1°C. A 7-day exposure period was followed by a 9-day depuration period. The dissolved PFOS concentration averaged 28 ng/L during the exposure period...
June 20, 2017: Bulletin of Environmental Contamination and Toxicology
https://www.readbyqxmd.com/read/28634536/telavancin-a-novel-semisynthetic-lipoglycopeptide-agent-to-counter-the-challenge-of-resistant-gram-positive-pathogens
#6
REVIEW
Biswadeep Das, Chayna Sarkar, Debasmita Das, Amit Gupta, Arnav Kalra, Shubham Sahni
Telavancin (TD-6424), a semisynthetic lipoglycopeptide vancomycin-derivative, is a novel antimicrobial agent developed by Theravance for overcoming resistant Gram-positive bacterial infections, specifically methicillin-resistant Staphylococcus aureus (MRSA). The US Food and Drug Administration (USFDA) had approved telavancin in 2009 for the treatment of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive bacteria, including MRSA (S. aureus, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus anginosus group, or Enterococcus faecalis)...
March 2017: Therapeutic Advances in Infectious Disease
https://www.readbyqxmd.com/read/28634062/site-directed-mutagenesis-of-gh10-xylanase-a-from-penicillium-canescens-for-determining-factors-affecting-the-enzyme-thermostability
#7
Yury A Denisenko, Alexander V Gusakov, Aleksandra M Rozhkova, Dmitry O Osipov, Ivan N Zorov, Veronika Yu Matys, Igor V Uporov, Arkady P Sinitsyn
In order to investigate factors affecting the thermostability of GH10 xylanase A from Penicillium canescens (PcXylA) and to obtain its more stable variant, the wild-type (wt) enzyme and its mutant forms, carrying single amino acid substitutions, were cloned and expressed in Penicillium verruculosum B1-537 (niaD-) auxotrophic strain under the control of the cbh1 gene promoter. The recombinant PcXylA-wt and I6V, I6L, L18F, N77D, Y125R, H191R, S246P, A293P mutants were successfully expressed and purified for characterization...
June 17, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28631484/ocular-pharmacokinetics-of-therapeutic-antibodies-given-by-intravitreal-injection-estimation-of-retinal-permeabilities-using-a-3-compartment-semi-mechanistic-model
#8
Laurence A Hutton-Smith, Eamonn A Gaffney, Helen M Byrne, Philip K Maini, Kapil Gadkar, Norman Alan Mazer
Intravitreally (IVT) injected macromolecules for the treatment of age-related macular degeneration must permeate through the inner limiting membrane (ILM) into the retina and through the retinal pigment epithelium (RPE) to enter the choroid. A quantitative understanding of intraocular transport mechanisms, elimination pathways and the effect of molecular size, is currently incomplete. We present a semi-mechanistic, 3-compartment (retina, vitreous and aqueous) pharmacokinetic (PK) model, expressed using linear ordinary differential equations (ODEs), to describe the molecular concentrations following a single IVT injection...
June 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28631076/effects-of-glycyrrhizic-acid-on-the-pharmacokinetics-of-pristimerin-in-rats-and-its-potential-mechanism
#9
Xiufen Zhao, Yan Wu, Dongmei Wang
BACKGROUND AND OBJECTIVES: Pristimerin has been reported to possess a wide range of pharmacological activities. This study investigates the effects of glycyrrhizic acid on the pharmacokinetics of pristimerin in rats. METHODS: The pharmacokinetics of orally administered pristimerin (2 mg/kg) with or without glycyrrhizic acid pretreatment (at a dose of 100 mg/kg/day for 7 days) were investigated. The plasma concentration of pristimerin was determined using a sensitive and reliable LC-MS/MS method, and the pharmacokinetics profiles were calculated and compared...
June 19, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28630197/pharmacodynamics-of-cefepime-combined-with-tazobactam-against-clinically-relevant-enterobactereaceae-in-a-neutropenic-mouse-thigh-model
#10
Maria J Melchers, Anita C van Mil, Claudia Lagarde, Jan den Hartigh, Johan W Mouton
The lack of new antibiotics prompted the investigation of the combination of two existing agents cefepime, a broad-spectrum cephalosporin and tazobactam to broaden its efficacy against extended-spectrum beta-lactamase producing Enterobacteriaceae. We determined the pharmacokinetic and pharmacodynamic properties of the combination in a murine neutropenic thigh model in order to establishing its exposure- response relationships (ERR). The PK of cefepime was determined for five doses; that of tazobactam was determined in earlier studies (Melchers et al Antimicrob...
June 19, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28628888/an-algorithm-for-filtering-detector-instabilities-in-search-of-novel-non-exponential-decay-and-in-conventional-half-life-determinations
#11
G W Hitt, B Goddard, A A Solodov, D Bridi, A F Isakovic, R El-Khazali
Recent reports of Solar modulation of beta-decay have reignited interest in whether or not radioactive half-lives are constants. A numerical approach for filtering instrumental effects on residuals is developed, using correlations with atmospheric conditions recorded while counting (204)Tl emissions with a Geiger-Müller counter. Half-life oscillations and detection efficiency oscillations can be separated provided their periods are substantially different. A partial uncertainty budget for the (204)Tl half-life shows significant decreases to medium-frequency instabilities correlated with pressure and temperature, which suggests that further development may aid general improvements in half-life determinations...
June 9, 2017: Applied Radiation and Isotopes
https://www.readbyqxmd.com/read/28628174/ranking-reach-registered-neutral-ionizable-and-ionic-organic-chemicals-based-on-their-aquatic-persistency-and-mobility
#12
H P H Arp, T N Brown, U Berger, S E Hale
The contaminants that have the greatest chances of appearing in drinking water are those that are mobile enough in the aquatic environment to enter drinking water sources and persistent enough to survive treatment processes. Herein a screening procedure to rank neutral, ionizable and ionic organic compounds for being persistent and mobile organic compounds (PMOCs) is presented and applied to the list of industrial substances registered under the EU REACH legislation as of December 2014. This comprised 5155 identifiable, unique organic structures...
June 19, 2017: Environmental Science. Processes & Impacts
https://www.readbyqxmd.com/read/28627339/-evaluation-of-adsorption-effect-of-activated-charcoal-on-oral-paraquat-poisoning-an-experimental-study-on-large-animal
#13
Baisheng Sun, Yuezhong He, Yuhao Pei, Cong Zhang, Xigang Zhang, Zhan Yang
OBJECTIVE: To study the adsorption effect of activated charcoal suspension on paraquat (PQ) in gastrointestinal tract of beagles exposed to PQ. METHODS: Twenty healthy male beagles were randomly divided into experimental group and control group, with 6 beagles in each group. 20% PQ solution (a dose of 30 mg/kg) was prescribed through stomach for beagles in both groups. After exposure to PQ for 30 minutes, the beagles in experimental group were given activated charcoal suspension (1...
March 2017: Zhonghua Wei Zhong Bing Ji Jiu Yi Xue
https://www.readbyqxmd.com/read/28626947/pharmacokinetic-study-of-bortezomib-administered-intravenously-in-taiwanese-patients-with-multiple-myeloma
#14
Shang-Yi Huang, Cheng-Shyong Chang, Ta-Chih Liu, Po-Nan Wang, Su-Peng Yeh, Ching-Liang Ho, Ming-Chung Kuo, Hsuan-Yu Lin, Jan de Jong, Jia-Yi Chen, Ya-Wen Yang
This phase 4, single-arm, non-randomized, open-label, post approval commitment study evaluated the pharmacokinetics and safety of bortezomib in Taiwanese patients with multiple myeloma. Patients (≥20 years) with measurable secretory multiple myeloma (serum monoclonal IgG ≥10, IgA/IgE ≥5, IgD ≥0.5 g/L, IgM present [regardless of level], and urine M protein of ≥200 mg/24 h) received intravenous bortezomib 1.3 mg/m(2) , twice weekly for 2 weeks, followed by a 10-day resting phase (days 12 to 21)...
June 19, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28626475/stereospecific-pharmacokinetic-characterization-of-liquiritigenin-in-the-rat
#15
Samaa Alrushaid, Neal M Davies, Stephanie E Martinez, Casey L Sayre
Liquiritigenin is a chiral flavonoid present in licorice and other medicinal plants. The nature of its biological fate with respect to the individual enantiomers has not been examined. In this study, we characterize, for the first time, the stereoselective pharmacokinetics of liquiritigenin. Liquiritigenin was intravenously (20 mg/kg) and orally (50 mg/kg) administered to male Sprague-Dawley rats (n = 4 per route of administration). Concentrations in serum and urine were characterized via stereospecific reversed-phase, isocratic HPLC method with UV detection...
June 2017: Research in Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28624438/the-metalloproteinase-adam10-a-useful-therapeutic-target
#16
REVIEW
Sebastian Wetzel, Lisa Seipold, Paul Saftig
Proteolytic cleavage represents a unique and irreversible posttranslational event regulating the function and half-life of many intracellular and extracellular proteins. The metalloproteinase ADAM10 has raised attention since it cleaves an increasing number of protein substrates close to the extracellular membrane leaflet. This "ectodomain shedding" regulates the turnover of a number of transmembrane proteins involved in cell adhesion and receptor signaling. It can initiate intramembrane proteolysis followed by nuclear transport and signaling of the cytoplasmic domain...
June 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28624367/evidence-for-revision-of-the-evaluated-half-life-of-207-bi
#17
L Pibida, L King
The National Institute of Standards and Technology (NIST) compared the measured full-energy peak efficiency obtained from a large set of sources to that of a (207)Bi source obtained using three different half-life values. The values of the half-life used for this comparison are published in the Decay Data Evaluation Project (32.9 ± 1.4) years and the Evaluated Nuclear Structure Data File (31.55 ± 0.4) years, and in a recent NIST publication (31.20 ± 0.05) years (or (11395 ± 18) days).
June 9, 2017: Applied Radiation and Isotopes
https://www.readbyqxmd.com/read/28624237/identification-of-syntaxin-4-as-an-essential-factor-for-the-hepatitis-c-virus-life-cycle
#18
Huimei Ren, Fabian Elgner, Kiyoshi Himmelsbach, Sami Akhras, Bingfu Jiang, Regina Medvedev, Daniela Ploen, Eberhard Hildt
Although there is evidence that multivesicular bodies (MVBs) are involved in the release of hepatitis C virus (HCV), many aspects of HCV release are still not fully understood. The amount of α-taxilin that prevents SNARE (soluble N-ethylmaleimidesensitive factor attachment protein receptor) complex formation by binding to free syntaxin 4 is reduced in HCV-positive cells. Therefore, it was analyzed whether the t-SNARE protein syntaxin 4 which mediates vesicles fusion is involved in the HCV life cycle. HCV-positive cells possess an increased amount of syntaxin 4 protein, although the amount of syntaxin 4-specific transcripts is decreased in HCV-positive Huh7...
June 10, 2017: European Journal of Cell Biology
https://www.readbyqxmd.com/read/28623878/in-vivo-characterisation-of-a-therapeutically-relevant-self-assembling-18-f-labelled-%C3%AE-sheet-forming-peptide-and-its-hydrogel-using-positron-emission-tomography
#19
O Morris, M A Elsawy, M Fairclough, K J Williams, A McMahon, J Grigg, D Forster, A F Miller, A Saiani, C Prenant
Positron emission tomography (PET) and fluorescence labelling have been used to assess the pharmacokinetics, biodistribution and eventual fate of a hydrogel-forming nonapeptide, FEFKFEFKK (F9) in healthy mice, using (18) F-labelled and fluoresceinisothiocyanate (FITC) - labelled F9 analogues. F9 was site-specifically radiolabelled with 2-[(18) F]fluoro-3-pyridinecarboxaldehyde ([(18) F]FPCA) via oxime bond formation. [(18) F]FPCA-F9 in vivo fate was evaluated both as a solution, following intravenous administration, and as a hydrogel when subcutaneously injected...
June 17, 2017: Journal of Labelled Compounds & Radiopharmaceuticals
https://www.readbyqxmd.com/read/28623508/clinical-pharmacokinetic-characteristics-of-cebranopadol-a-novel-first-in-class-analgesic
#20
Elke Kleideiter, Chiara Piana, Shaonan Wang, Robert Nemeth, Michael Gautrois
BACKGROUND AND OBJECTIVES: Cebranopadol is a novel first-in-class analgesic acting as a nociceptin/orphanin FQ peptide and opioid peptide receptor agonist with central analgesic activity. It is currently in clinical development for the treatment of chronic pain conditions. This trial focuses on the clinical pharmacokinetic (PK) properties of cebranopadol after oral single- and multiple-dose administration. METHODS: The basic PK properties of cebranopadol were assessed by means of noncompartmental methods in six phase I clinical trials in healthy subjects and patients...
June 16, 2017: Clinical Pharmacokinetics
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