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https://www.readbyqxmd.com/read/27936446/design-synthesis-and-evaluation-of-4-aminoquinoline-purine-hybrids-as-potential-antiplasmodial-agents
#1
P Linga Reddy, Shabana I Khan, Prija Ponnan, Mohit Tripathi, Diwan S Rawat
A novel series of 4-aminoquinoline-purine hybrids were synthesized and assessed for their antiplasmodial activity against CQ-sensitive and CQ-resistant strains of P. falciparum. It was envisaged that linking of the 4-aminoquinoline pharmacophore (targeting heme-detoxification pathway of malarial parasite) with the purine functionality (targeting plasmodial HG(X)PRT enzyme) will produce a hybrid antiplasmodial agent with increased potency. The synthesized hybrids displayed good antiplasmodial activities against both the sensitive and resistant strains of P...
December 1, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27936445/synthesis-and-antifungal-activity-of-novel-indole-replaced-streptochlorin-analogues
#2
Ming-Zhi Zhang, Chen-Yang Jia, Yu-Cheng Gu, Nick Mulholland, Sarah Turner, David Beattie, Wei-Hua Zhang, Guang-Fu Yang, John Clough
Based on examples of the successful applications in drug discovery of bioisosterism, a series of streptochlorin analogues in which indole has been replaced by other heterocycles has been designed and synthesized, as a continuation of our studies aimed at the discovery of novel streptochlorin analogues with improved antifungal activity. Biological testing showed that most of the indole-replaced streptochlorin analogues were inactive, though compound 6f had a broad spectrum of antifungal activity with significant activity against Alternaria solani...
December 2, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27936416/antigen-recognition-triggered-drug-delivery-mediated-by-nanocapsule-functionalized-cytotoxic-t-cells
#3
R Brad Jones, Stephanie Mueller, Sudha Kumari, Vlad Vrbanac, Shy Genel, Andrew M Tager, Todd M Allen, Bruce D Walker, Darrell J Irvine
Cytotoxic T-Lymphocytes (CTLs) kill pathogen-infected or transformed cells following interaction of their T-cell receptors (TCRs) with foreign (e.g. virus-derived) peptides bound to MHC-I molecules on the target cell. TCR binding triggers CTLs to secrete perforin, which forms pores in the target cell membrane, promoting target death. Here, we show that by conjugating drug-loaded lipid nanoparticles to the surface of CTLs, their lytic machinery can be co-opted to lyse the cell-bound drug carrier, providing triggered release of drug cargo upon target cell recognition...
November 25, 2016: Biomaterials
https://www.readbyqxmd.com/read/27936388/nanoliposome-encapsulated-anesthetics-for-local-anesthesia-application
#4
REVIEW
Sepideh Vahabi, Ali Eatemadi
The systemic administration of opioids leads to potentially severe and undesirable and side effects like sedation and drowsiness, vomiting and nausea, allergies, respiratory depression, and neutrophil dysfunction. The application of nanotechnology in medical field has drawn a great attention in recent times. Several treatments available are tedious and expensive. Application of nanotechnology brings about faster cure and cost effectiveness. Nanoliposomes are one of the widely used names for nanoparticles used in medicine...
December 6, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27936172/tamoxifen-isomers-and-metabolites-exhibit-distinct-affinity-and-activity-at-cannabinoid-receptors-potential-scaffold-for-drug-development
#5
Benjamin M Ford, Lirit N Franks, Anna Radominska-Pandya, Paul L Prather
Tamoxifen (Tam) is a selective estrogen receptor (ER) modulator (SERM) that is an essential drug to treat ER-positive breast cancer. Aside from known actions at ERs, recent studies have suggested that some SERMs like Tam also exhibit novel activity at cannabinoid subtype 1 and 2 receptors (CB1R and CB2Rs). Interestingly, cis- (E-Tam) and trans- (Z-Tam) isomers of Tam exhibit over a 100-fold difference in affinity for ERs. Therefore, the current study assessed individual isomers of Tam and subsequent cytochrome P450 metabolic products, 4-hydroxytamoxifen (4OHT) and 4-hydroxy-N-desmethyl tamoxifen (End) for affinity and activity at CBRs...
2016: PloS One
https://www.readbyqxmd.com/read/27936138/diffusion-based-design-of-multi-layered-ophthalmic-lenses-for-controlled-drug-release
#6
Andreia F R Pimenta, Ana Paula Serro, Patrizia Paradiso, Benilde Saramago, Rogério Colaço
The study of ocular drug delivery systems has been one of the most covered topics in drug delivery research. One potential drug carrier solution is the use of materials that are already commercially available in ophthalmic lenses for the correction of refractive errors. In this study, we present a diffusion-based mathematical model in which the parameters can be adjusted based on experimental results obtained under controlled conditions. The model allows for the design of multi-layered therapeutic ophthalmic lenses for controlled drug delivery...
2016: PloS One
https://www.readbyqxmd.com/read/27936112/genome-wide-association-of-heroin-dependence-in-han-chinese
#7
Gursharan Kalsi, Jack Euesden, Jonathan R I Coleman, Francesca Ducci, Fazil Aliev, Stephen J Newhouse, Xiehe Liu, Xiaohong Ma, Yingcheng Wang, David A Collier, Philip Asherson, Tao Li, Gerome Breen
Drug addiction is a costly and recurring healthcare problem, necessitating a need to understand risk factors and mechanisms of addiction, and to identify new biomarkers. To date, genome-wide association studies (GWAS) for heroin addiction have been limited; moreover they have been restricted to examining samples of European and African-American origin due to difficulty of recruiting samples from other populations. This is the first study to test a Han Chinese population; we performed a GWAS on a homogeneous sample of 370 Han Chinese subjects diagnosed with heroin dependence using the DSM-IV criteria and 134 ethnically matched controls...
2016: PloS One
https://www.readbyqxmd.com/read/27935770/from-breast-cancer-to-antimicrobial-combating-extremely-resistant-gram-negative-superbugs-using-novel-combinations-of-polymyxin-b-with-selective-estrogen-receptor-modulators
#8
Maytham H Hussein, Elena K Schneider, Alysha G Elliott, Meiling Han, Felisa Reyes-Ortega, Faye Morris, Mark A T Blastovich, Raad Jasim, Bart Currie, Mark Mayo, Mark Baker, Matthew A Cooper, Jian Li, Tony Velkov
Novel therapeutic approaches are urgently needed to combat nosocomial infections caused by extremely drug-resistant (XDR) "superbugs." This study aimed to investigate the synergistic antibacterial activity of polymyxin B in combination with selective estrogen receptor modulators (SERMs) against problematic Gram-negative pathogens. In vitro synergistic antibacterial activity of polymyxin B and the SERMs tamoxifen, raloxifene, and toremifene was assessed using the microdilution checkerboard and static time-kill assays against a panel of Gram-negative isolates...
December 9, 2016: Microbial Drug Resistance: MDR: Mechanisms, Epidemiology, and Disease
https://www.readbyqxmd.com/read/27935479/structural-basis-for-subtype-specific-inhibition-of-the-p2x7-receptor
#9
Akira Karasawa, Toshimitsu Kawate
The P2X7 receptor is a non-selective cation channel activated by extracellular adenosine triphosphate (ATP). Chronic activation of P2X7 underlies many health problems such as pathologic pain, yet we lack effective antagonists due to poorly understood mechanisms of inhibition. Here we present crystal structures of a mammalian P2X7 receptor complexed with five structurally-unrelated antagonists. Unexpectedly, these drugs all bind to an allosteric site distinct from the ATP-binding pocket in a groove formed between two neighboring subunits...
December 9, 2016: ELife
https://www.readbyqxmd.com/read/27935018/tolerability-and-efficacy-of-perampanel-in-children-with-refractory-epilepsy
#10
Eli Heyman, Eli Lahat, Noa Levin, Orna Epstein, Mirit Lazinger, Matitiahu Berkovitch, Revital Gandelman-Marton
AIM: There are few reports on the tolerability and efficacy of perampanel, a new antiepileptic drug with a novel mechanism of action, in children and adolescents. We aimed to describe our experience with perampanel add-on and mono-therapy in children with refractory epilepsy. METHOD: Computerized medical records of children treated with perampanel in the paediatric neurology clinic from December 2012 to October 2015 were reviewed. RESULTS: Twenty-four children treated with perampanel (15 females, 9 males) aged 1 year 6 months to 17 years (mean 10y, standard deviation [SD] 4y 5mo) were identified...
December 9, 2016: Developmental Medicine and Child Neurology
https://www.readbyqxmd.com/read/27934927/sensitisation-of-an-azole-resistant-aspergillus-fumigatus-strain-containing-the-cyp51a-related-mutation-by-deleting-the-srba-gene
#11
Daisuke Hagiwara, Akira Watanabe, Katsuhiko Kamei
Azoles are widely used for controlling fungal growth in both agricultural and medical settings. The target protein of azoles is CYP51, a lanosterol 14-α-demethylase involved in the biosynthesis of ergosterol. Recently, a novel azole resistance mechanism has arisen in pathogenic fungal species Aspergillus fumigatus. Resistant strains contain a 34-bp or 46-bp tandem repeat (TR) in the promoter of cyp51A, and have disseminated globally in a short period of time. In this study, we investigated whether an azole-resistant strain with a 46-bp TR (TR46/Y121F/T289A) could be sensitised to azoles by deletion of srbA, encoding a direct regulator of cyp51A...
December 9, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27934920/functional-human-induced-hepatocytes-hiheps-with-bile-acid-synthesis-and-transport-capacities-a-novel-in-vitro-cholestatic-model
#12
Xuan Ni, Yimeng Gao, Zhitao Wu, Leilei Ma, Chen Chen, Le Wang, Yunfei Lin, Lijian Hui, Guoyu Pan
Drug-induced cholestasis is a leading cause of drug withdrawal. However, the use of primary human hepatocytes (PHHs), the gold standard for predicting cholestasis in vitro, is limited by their high cost and batch-to-batch variability. Mature hepatocyte characteristics have been observed in human induced hepatocytes (hiHeps) derived from human fibroblast transdifferentiation. Here, we evaluated whether hiHeps could biosynthesize and excrete bile acids (BAs) and their potential as PHH alternatives for cholestasis investigations...
December 9, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27934796/plga-loaded-nanomedicines-in-melanoma-treatment-future-prospect-for-efficient-drug-delivery
#13
REVIEW
Sreemanti Das, Anisur Rahman Khuda-Bukhsh
Current treatment methods for melanoma have some limitations such as less target-specific action, severe side effects and resistance to drugs. Significant progress has been made in exploring novel drug delivery systems based on suitable biochemical mechanisms using nanoparticles ranging from 10 to 400 nm for drug delivery and imaging, utilizing their enhanced penetration and retention properties. Poly-lactide-co-glycolide (PLGA), a copolymer of poly-lactic acid and poly-glycolic acid, provides an ideally suited performance-based design for better penetration into skin cells, thereby having a greater potential for the treatment of melanoma...
August 2016: Indian Journal of Medical Research
https://www.readbyqxmd.com/read/27934635/metabolism-of-the-mek1-2-inhibitor-pimasertib-involves-a-novel-conjugation-with-phospho-ethanolamine-in-patients-with-solid-tumors
#14
Holger Scheible, Friedrich Kraetzer, Andreas Marx, Andreas Johne, Elmar Wimmer
Pimasertib (AS703026 or MSC1936369B) is a selective inhibitor of MEK1/2, the mitogen-activated protein kinase (MAPK) signaling pathway, which is often dysregulated in cancer cells. Pimasertib has shown potent preclinical anti tumor activity and its clinical activity is being investigated in various tumor types. In this phase I study, the disposition and biotransformation of (14)C-radiolabeled pimasertib was investigated in six patients with locally advanced or metastatic solid tumors (NCT 01713036). Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) and radiodetection techniques were used to investigate the profiles and structures of metabolites in plasma, urine and feces after a single oral dose of (14)C-pimasertib...
December 1, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27934109/in-vivo-biotransformation-of-the-fusion-protein-tetranectin-apolipoprotein-a1-analyzed-by-ligand-binding-mass-spectrometry-combined-with-quantitation-by-elisa
#15
Manfred Zell, Christophe Husser, Roland F Staack, Gregor Jordan, Wolfgang F Richter, Simone Schadt, Axel Pähler
The in vivo biotransformation of a novel fusion protein tetranectin/apolipoprotein A1 (TN-ApoA1) was investigated by ligand-binding mass spectrometry (LB-MS) in support of enzyme-linked immunosorbent assays (ELISA). The main focus was on catabolites formed by proteolysis of the fusion protein in rabbit following intravenous administration of lipidated TN-ApoA1. The drug and its catabolites were isolated from rabbit plasma by immunocapture with a monoclonal antibody (mAb) binding to the fusion region of TN-ApoA1...
December 6, 2016: Analytical Chemistry
https://www.readbyqxmd.com/read/27933968/emissive-h-aggregates-of-an-ultrafast-molecular-rotor-a-promising-platform-for-sensing-heparin
#16
Niyati H Mudliar, Prabhat K Singh
Constructing "turn on" fluorescent probes for heparin, a most widely used anticoagulant in clinics, from commercially available materials is of great importance, but remains challenging. Here, we report the formation of a rarely observed emissive H-aggregate of an ultrafast molecular rotor dye, Thioflavin-T, in the presence of heparin, which provides an excellent platform for simple, economic and rapid fluorescence turn-on sensing of heparin. Generally, H-aggregates are considered as serious problem in the field of biomolecular sensing, owing to their poorly emissive nature resulting from excitonic interaction...
November 23, 2016: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/27933962/design-synthesis-and-pharmacological-characterization-of-2-2-furanyl-thiazolo-5-4-d-pyrimidine-5-7-diamine-derivatives-new-highly-potent-a2a-adenosine-receptor-inverse-agonists-with-antinociceptive-activity
#17
Flavia Varano, Daniela Catarzi, Fabrizio Vincenzi, Marco Betti, Matteo Falsini, Annalisa Ravani, Pier Andrea Borea, Vittoria Colotta, Katia Varani
In this study, we describe the design and synthesis of new N(5)-substituted-2-(2-furanyl) thiazolo[5,4-d]pyrimidine-5,7-diamines (2-18) and their pharmacological characterization as A2A adenosine receptor (AR) antagonists by using in vitro and in vivo assays. In competition binding experiments two derivatives (13 and 14) emerged as outstanding ligands showing two different affinity values (KH and KL) for the hA2A receptor with the high affinity KH value in the femtomolar range. The in vitro functional activity assays, performed by using cyclic AMP experiments, assessed that they behave as potent inverse agonists at the hA2A AR...
December 8, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27933945/fragment-based-approach-to-the-development-of-an-orally-bioavailable-lactam-inhibitor-of-lipoprotein-associated-phospholipase-a2-lp-pla2
#18
Alison J-A Woolford, Philip J Day, Véronique Bénéton, Valerio Berdini, Joseph E Coyle, Yann Dudit, Pascal Grondin, Pascal Huet, Lydia Y W Lee, Eric S Manas, Rachel L McMenamin, Christopher W Murray, Lee W Page, Vipulkumar K Patel, Florent Potvain, Sharna J Rich, Yingxia Sang, Don O Somers, Lionel Trottet, Zehong Wan, Xiaomin Zhang
Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity...
December 8, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27933932/mechanism-of-the-pseudoirreversible-binding-of-amantadine-to-the-m2-proton-channel
#19
Salomé Llabrés, Jordi Juárez-Jiménez, Matteo Masetti, Rosana Leiva, Santiago Vázquez, Sabrina Gazzarrini, Anna Moroni, Andrea Cavalli, F Javier Luque
The M2 proton channel of influenza A virus is an integral membrane protein involved in the acidification of the viral interior, a step necessary for the release of the viral genetic material and replication of new virions. The aim of this study is to explore the mechanism of drug (un)binding to the M2 channel in order to gain insight into the structural and energetic features relevant for the development of novel inhibitors. To this end, we have investigated the binding of amantadine (Amt) to the wild type (wt) M2 channel and its V27A variant using multiple independent molecular dynamics simulations, exploratory conventional metadynamics, and multiple-walkers well-tempered metadynamics calculations...
November 30, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27933931/imaging-and-quantitation-of-a-succession-of-transient-intermediates-reveal-the-reversible-self-assembly-pathway-of-a-simple-icosahedral-virus-capsid
#20
María Medrano, Miguel Ángel Fuertes, Alejandro Valbuena, Pablo J P Carrillo, Alicia Rodríguez-Huete, Mauricio G Mateu
Understanding the fundamental principles underlying supramolecular self-assembly may facilitate many developments, from novel antivirals to self-organized nanodevices. Icosahedral virus particles constitute paradigms to study self-assembly using a combination of theory and experiment. Unfortunately, assembly pathways of the structurally simplest virus capsids, those more accessible to detailed theoretical studies, have been difficult to study experimentally. We have enabled the in vitro self-assembly under close to physiological conditions of one of the simplest virus particles known, the minute virus of mice (MVM) capsid, and experimentally analyzed its pathways of assembly and disassembly...
November 30, 2016: Journal of the American Chemical Society
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