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https://www.readbyqxmd.com/read/28526836/characterisation-of-antibiotic-prescriptions-for-acute-respiratory-tract-infections-in-danish-general-practice-a-retrospective-registry-based-cohort-study
#1
Rune Aabenhus, Malene Plejdrup Hansen, Laura Trolle Saust, Lars Bjerrum
Inappropriate use of antibiotics is contributing to the increasing rates of antimicrobial resistance. Several Danish guidelines on antibiotic prescribing for acute respiratory tract infections in general practice have been issued to promote rational prescribing of antibiotics, however it is unclear if these recommendations are followed. We aimed to characterise the pattern of antibiotic prescriptions for patients diagnosed with acute respiratory tract infections, by means of electronic prescriptions, labeled with clinical indications, from Danish general practice...
May 19, 2017: NPJ Primary Care Respiratory Medicine
https://www.readbyqxmd.com/read/28526743/systematic-identification-of-functional-residues-of-artemisia-annua-amorpha-4-11-diene-synthase
#2
Xin Fang, Jian-Xu Li, Jin-Quan Huang, You-Li Xiao, Peng Zhang, Xiao-Ya Chen
Terpene synthases (TPSs) are responsible for the extremely diversified and complex structure of terpenoids. Amorpha-4,11-diene synthase (ADS) has a high (90%) fidelity in generating the sesquiterpene precursor for biosynthesis of artemisinin, an antimalarial drug, however, little is known about how active site residues of ADS involved in the carbocation rearrangement and cyclization reactions. Here, we identify seven residues that are key to most of the catalytic steps in ADS. By structural modeling and amino acid sequence alignments of ADS with two functionally relevant sesquiterpene synthases from Artemisia annua, we performed site-directed mutagenesis and found that a single substitution, T296V, impaired the ring closure activity almost completely, and tetra-substitutions (L374Y/L404V/L405I/G439S) led to an enzyme generating 80% monocyclic bisabolyl-type sesquiterpenes, whereas a double mutant (T399L/T447G) showed compromised activity in regioselective deprotonation to yield 34...
May 19, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28525268/rational-design-of-novel-allosteric-dihydrofolate-reductase-inhibitors-showing-antibacterial-effects-on-drug-resistant-e-coli-escape-variants
#3
Bharath Srinivasan, João V Rodrigues, Sam Tonddast-Navaei, Eugene Shakhnovich, Jeffrey Skolnick
In drug-discovery, systematic variations of substituents on a common scaffold and bioisosteric replacements are often used to generate diversity and obtain molecules with better biological effects. However, this could saturate the small-molecule diversity pool resulting in drug-resistance. On the other hand, conventional drug-discovery relies on targeting known pockets on protein surfaces leading to drug resistance by mutations of critical pocket residues. Here, we present a two-pronged strategy of designing novel drugs that target unique pockets on a protein's surface to overcome the above problems...
May 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28520909/large-scale-data-driven-integrative-framework-for-extracting-essential-targets-and-processes-from-disease-associated-gene-data-sets
#4
Gaston K Mazandu, Emile R Chimusa, Kayleigh Rutherford, Elsa-Gayle Zekeng, Zoe Z Gebremariam, Maryam Y Onifade, Nicola J Mulder
Populations worldwide currently face several public health challenges, including growing prevalence of infections and the emergence of new pathogenic organisms. The cost and risk associated with drug development make the development of new drugs for several diseases, especially orphan or rare diseases, unappealing to the pharmaceutical industry. Proof of drug safety and efficacy is required before market approval, and rigorous testing makes the drug development process slow, expensive and frequently result in failure...
May 18, 2017: Briefings in Bioinformatics
https://www.readbyqxmd.com/read/28516413/self-emulsification-of-lipidic-drug-delivery-system-in-pure-water-and-in-concentrated-glycerol-solution
#5
Carole Planchette, Annalisa Mercuri, Lorenzo Arcangeli, Manfred Kriechbaum, Peter Laggner
Self-emulsifying drug delivery systems (SEDDS), often intended for oral delivery, are normally explored in biorelevant aqueous media. The high complexity of these multi-component systems leaves the understanding of self-emulsification poor, hindering formulation rationalization. In this work, we aimed to fill this gap by studying the effects of glycerol on the self-emulsification of a ternary component formulation made of 20% w/w Tween 80, 15% w/w Span 80, and 65% w/w Captex 300 Low C6. The behavior of SEDDS in pure water and a binary mixture of water and glycerol (58...
May 17, 2017: AAPS PharmSciTech
https://www.readbyqxmd.com/read/28513287/contact-force-technology-integrated-with-3d-navigation-system-for-atrial-fibrillation-ablation-improving-results
#6
Roberto Rordorf, Antonio Sanzo, Vincenzo Gionti
Pulmonary veins isolation (PVI) by radiofrequency (RF) ablation is currently an established treatment for symptomatic, drug-resistant paroxysmal atrial fibrillation. Although the effectiveness of the therapy has been clearly demonstrated, success rate after a single procedure is still sub-optimal. The main reason for recurrences after PVI is electrical pulmonary vein-atrium reconnection. In order to increase the likelihood of permanent PVI, the creation of a transmural, durable lesion is mandatory. The main determinants of lesion size and transmurality are power, stability, duration and contact-force during RF application...
May 17, 2017: Expert Review of Medical Devices
https://www.readbyqxmd.com/read/28510797/influence-of-morbid-obesity-on-the-pharmacokinetics-of-morphine-morphine-3-glucuronide-and-morphine-6-glucuronide
#7
Sjoerd de Hoogd, Pyry A J Välitalo, Albert Dahan, Simone van Kralingen, Michael M W Coughtrie, Eric P A van Dongen, Bert van Ramshorst, Catherijne A J Knibbe
INTRODUCTION: Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers. METHODS: In this analysis, data from 20 morbidly obese patients [mean body mass index 49.9 kg/m(2) (range 37...
May 16, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28508178/survey-about-the-use-of-clarithromycin-in-an-ent-outpatient-department-of-a-tertiary-hospital
#8
Jingchao Yan, Jianwen Shen, Ying Li, Fengmin Tang, Nianzu Chen
We undertook this survey about the use of clarithromycin in the Ear, Nose, and Throat (ENT) Outpatient Department of Fudan University Hospital to understand its utilization patterns and rational use. A survey of prescriptions given to outpatients was carried out, and detailed information of the patients, including age, sex, diagnosis, combined medication, and other information, was recorded in Excel spreadsheets. The rationale for each prescription was evaluated retrospectively. Based on our analysis, 82.5% of the clarithromycin prescriptions were for the treatment of rhinosinusitis...
May 15, 2017: European Archives of Oto-rhino-laryngology
https://www.readbyqxmd.com/read/28507948/characterizing-the-hot-spots-involved-in-ron-msp%C3%AE-complex-formation-using-in-silico-alanine-scanning-mutagenesis-and-molecular-dynamics-simulation
#9
Omid Zarei, Maryam Hamzeh-Mivehroud, Silvia Benvenuti, Fulya Ustun-Alkan, Siavoush Dastmalchi
Purpose: Implication of protein-protein interactions (PPIs) in development of many diseases such as cancer makes them attractive for therapeutic intervention and rational drug design. RON (Recepteur d'Origine Nantais) tyrosine kinase receptor has gained considerable attention as promising target in cancer therapy. The activation of RON via its ligand, macrophage stimulation protein (MSP) is the most common mechanism of activation for this receptor. The aim of the current study was to perform in silico alanine scanning mutagenesis and to calculate binding energy for prediction of hot spots in protein-protein interface between RON and MSPβ chain (MSPβ)...
April 2017: Advanced Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28507435/mesoporous-silica-nanoparticles-trigger-mitophagy-in-endothelial-cells-and-perturb-neuronal-network-activity-in-a-size-and-time-dependent-manner
#10
Antonina Orlando, Emanuela Cazzaniga, Maria Tringali, Francesca Gullo, Andrea Becchetti, Stefania Minniti, Francesca Taraballi, Ennio Tasciotti, Francesca Re
PURPOSE: Mesoporous silica nanoparticles (MSNPs) are excellent candidates for biomedical applications and drug delivery to different human body areas, the brain included. Although toxicity at cellular level has been investigated, we are still far from using MSNPs in the clinic, because the mechanisms involved in the cellular responses activated by MSNPs have not yet been elucidated. MATERIALS AND METHODS: This study used an in vitro multiparametric approach to clarify relationships among size, dose, and time of exposure of MSNPs (0...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/28506671/modeling-of-flux-binding-and-substitution-of-urea-molecules-in-the-urea-transporter-dvut
#11
Hai-Tian Zhang, Zhe Wang, Tao Yu, Jian-Ping Sang, Xian-Wu Zou, Xiaoqin Zou
Urea transporters (UTs) are transmembrane proteins that transport urea molecules across cell membranes and play a crucial role in urea excretion and water balance. Modeling the functional characteristics of UTs helps us understand how their structures accomplish the functions at the atomic level, and facilitates future therapeutic design targeting the UTs. This study was based on the crystal structure of Desulfovibrio vulgaris urea transporter (dvUT). To model the binding behavior of urea molecules in dvUT, we constructed a cooperative binding model...
April 25, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28506090/rational-design-strategies-for-fimh-antagonists-new-drugs-on-the-horizon-for-urinary-tract-infection-and-crohn-s-disease
#12
Laurel K Mydock-McGrane, Thomas J Hannan, James W Janetka
The bacterial adhesin FimH is a virulence factor and an attractive therapeutic target for urinary tract infection (UTI) and Crohn's Disease (CD). Located on type 1 pili of uropathogenic E. coli (UPEC), the FimH adhesin plays an integral role in the pathogenesis of UPEC. Recent efforts have culminated in the development of small-molecule mannoside FimH antagonists that target the mannose-binding lectin domain of FimH, inhibiting its function and preventing UPEC from binding mannosylated host cells in the bladder, thereby circumventing infection...
May 16, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28506066/de-novo-computational-design-for-development-of-a-peptide-ligand-oriented-to-vegfr-3-with-high-affinity-and-long-circulation
#13
Hong M Li, Zhi P Dong, Qi Y Wang, Li X Liu, Bing X Li, Xiao N Ma, Ming S Lin, Tao Lu, Yue Wang
The overexpression of VEGFR-3 is correlated with a worse prognosis in lung cancer and has been regarded as a rational target for specific drug delivery. Here, VEGFR-3 homing peptide library was efficiently established by computational design. Strong fluorescent signal of selected peptides were observed in A549 cells, but much weaker in other cells. The positive immunostaining overlapped with VEGFR-3 confirmed high affinity and selectivity of one novel peptide (CP-7). In addition, cell uptake of FITC-CP-7 peptide was significantly blocked by co-injection of excess CP-7 peptide...
May 16, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28504895/progress-toward-inhibitors-of-metallo-%C3%AE-lactamases
#14
Ross P McGeary, Daniel Tc Tan, Gerhard Schenk
The global overuse of antibiotics has led to the emergence of drug-resistant pathogenic bacteria. Bacteria can combat β-lactams by expressing β-lactamases. Inhibitors of one class of β-lactamase, the serine-β-lactamases, are used clinically to prevent degradation of β-lactam antibiotics. However, a second class of β-lactamase, the metallo-β-lactamases (MBLs), function by a different mechanism to serine-β-lactamases and no inhibitors of MBLs have progressed to be used in the clinic. Bacteria that express MBLs are an increasingly important threat to human health...
May 15, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28503546/computational-tool-for-fast-in-silico-evaluation-of-herg-k-channel-affinity
#15
Giulia Chemi, Sandra Gemma, Giuseppe Campiani, Simone Brogi, Stefania Butini, Margherita Brindisi
The development of a novel comprehensive approach for the prediction of hERG activity is herein presented. Software Phase has been used to derive a 3D-QSAR model, employing as alignment rule a common pharmacophore built on a subset of 22 highly active compounds (threshold Ki: 50 nM) against hERG K(+) channel. Five features comprised the pharmacophore: two aromatic rings (R1 and R2), one hydrogen-bond acceptor (A), one hydrophobic site (H), and one positive ionizable function (P). The sequential 3D-QSAR model developed with a set of 421 compounds (randomly divided in training and test set) yielded a test set (Q(2)) = 0...
2017: Frontiers in Chemistry
https://www.readbyqxmd.com/read/28500273/fundamental-trade-offs-between-information-flow-in-single-cells-and-cellular-populations
#16
Ryan Suderman, John A Bachman, Adam Smith, Peter K Sorger, Eric J Deeds
Signal transduction networks allow eukaryotic cells to make decisions based on information about intracellular state and the environment. Biochemical noise significantly diminishes the fidelity of signaling: networks examined to date seem to transmit less than 1 bit of information. It is unclear how networks that control critical cell-fate decisions (e.g., cell division and apoptosis) can function with such low levels of information transfer. Here, we use theory, experiments, and numerical analysis to demonstrate an inherent trade-off between the information transferred in individual cells and the information available to control population-level responses...
May 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28500170/jak2-inhibitors-for-myeloproliferative-neoplasms-what-is-next
#17
Prithviraj Bose, Srdan Verstovsek
Since its approval in 2011, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant/intolerant polycythemia vera (PV) is steadily increasing. A number of other JAK2 inhibitors have entered clinical testing, but none has been approved yet, and many discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, where survival is short...
May 12, 2017: Blood
https://www.readbyqxmd.com/read/28495568/quantitative-analyses-of-the-influence-of-parameters-governing-rate-determining-process-of-hepatic-elimination-of-drugs-on-the-magnitudes-of-drug-drug-interactions-via-hepatic-oatps-and-cyp3a-using-physiologically-based-pharmacokinetic-models
#18
Takashi Yoshikado, Maeda Kazuya, Hiroyuki Kusuhara, Ken-Ichi Furihata, Yuichi Sugiyama
Physiologically-based pharmacokinetic (PBPK) models were constructed for hepatic organic anion transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) substrates (bosentan, repaglinide, clarithromycin, and simeprevir), a CYP3A probe substrate (midazolam), and selective inhibitors for OATPs (rifampicin) and CYP3A (itraconazole), though the role of OATPs in the hepatic uptake of clarithromycin is unclear. The pharmacokinetic data were obtained from our previous clinical drug-drug interaction (DDI) study...
May 8, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28495384/medicinal-chemistry-of-antischistosomal-drugs-praziquantel-and-oxamniquine
#19
REVIEW
Vinícius Barros Ribeiro da Silva, Bruna Rafaella Koresch Leiva Campos, Jamerson Ferreira de Oliveira, Jean-Luc Decout, Maria do Carmo Alves de Lima
Neglected tropical diseases (NTDs) are a group of diseases that, besides prevailing in poverty conditions, contribute to the maintenance of social inequality, being a strong barrier to a country development. Schistosomiasis, a NTD, is a tropical and subtropical disease caused by the trematode Schistosoma mansoni (Africa, Middle East, Caribbean, Brazil, Venezuela, Suriname), japonicum (China, Indonesia, the Philippines), mekongi (several districts of Cambodia and the Lao People's Democratic Republic), intercalatum and guianensis (areas of tropical rainforests in Central Africa) and hematobium (Middle East Africa, Corsica, France) whose adult forms inhabit the mesenteric vessels of the host, while the intermediate forms are found in the aquatic gastropod snails of the genus Biomphalaria...
April 27, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28494724/c-type-lectin-receptor-old-friend-and-new-player
#20
Hai Hou, Yahui Guo, Qing Chang, Tianming Luo, Xin Wu, Xueqiang Zhao
During the last two decades, C-type lectin receptors (CLRs) have been demonstrated to play key roles in initiating the host immune response upon fungal infection. It is well established that CLRs, such as Dectin-1, Dectin-2, Dectin-3 and Mincle, recognize the cell wall component from the infected microorganisms by using their carbohydrate recognition domain (CRD). Upon stimulation, CLRs induce multiple signal transduction cascades through their own immune-receptor tyrosine-based activation motifs (ITAMs) or interacting with ITAM-containing adaptor proteins such as FcRγ, which then lead to the activation of nuclear factor kappa B (NF-kB) through Syk- and CARD9-dependent pathway...
May 9, 2017: Medicinal Chemistry
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