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New Drug Development

Vanesa Nozal, Ana Martinez
Tau-tubuline kinases (TTBK) are a family of serine/threonine and tyrosine kinases recently discovered and implicated in the phosphorylation of important substrates such as tau, tubuline or TDP-43. Its two homologs, TTBK1 and TTBK2, show different expression patterns and different involvements in physiological mechanisms of great importance such as mitosis, ciliogenesis and neurotransmission. Their phosphorylation activity has also linked them to the development of neurodegenerative diseases like Alzheimer's disease, amyotrophic lateral sclerosis or spinocerebellar ataxia type 11...
October 15, 2018: European Journal of Medicinal Chemistry
Alessandro Palmioli, Sara Bertuzzi, Ada De Luigi, Laura Colombo, Barbara La Ferla, Mario Salmona, Ivano De Noni, Cristina Airoldi
The growing interest in medicinal plants for the identification of new bioactive compounds and the formulation of new nutraceuticals and drugs prompted us to develop a powerful experimental approach allowing the detailed metabolic profiling of complex plant extracts, the identification of ligands of macromolecular targets of biomedical relevance and a preliminary characterization of their biological activity. To this end, we selected Peucedanum ostruthium, a plant traditionally employed in Austria and Italy for its several potential therapeutic applications, as case study...
October 12, 2018: Bioorganic Chemistry
Abhijit Mukherjee, Suvranil Ghosh, Rudraditya Sarkar, Satyajit Samanta, Sudipta Ghosh, Mahadeb Pal, Adinath Majee, Sukanta Kumar Sen, Bula Singh
In the progress of small molecule as drug candidates, 4-hydroxycoumarin based compounds bearing a crucial place as potent antibiotic agents with appreciable safety in drug invention. Being synthetically and easily obtainable, 4-hydroxycoumarin related compounds with planar structure have been promoted predominantly as DNA targeting agent. Nevertheless, here we elucidate the synthesis, characterization and theoretical study of bio-active small molecule 4-hydroxy-3,4'-bichromenyl-2,2'-dione (4HBD). Then we have illuminated the binding interactions of 4HBD with calf thymus DNA (ctDNA), which is particularly designed for biological application...
October 13, 2018: Journal of Photochemistry and Photobiology. B, Biology
Cécile Apel, Jérôme Bignon, Maria Conception García Alvarez, Sarah Ciccone, Patricia Clerc, Isabelle Grondin, Emmanuelle Girard-Valenciennes, Jacqueline Smadja, Philippe Lopes, Michel Frederich, Fanny Roussi, Thierry Meinnel, Carmela Giglione, Marc Litaudon
N-myristoylation (Myr) is an eukaryotic N-terminal co- or post-translational protein modification in which the enzyme N-myristoyltransferase (NMT) transfers a fatty acid (C14:0) to the N-terminal glycine residues of several cellular key proteins. Depending on the cellular context, NMT may serve as a molecular target in anticancer or anti-infectious therapy, and drugs that inhibit this enzyme may be useful in the treatment of cancer or infectious diseases. As part of an on-going project to identify natural Homo sapiens N-myristoyltransferase 1 inhibitors (HsNMT1), two ellagitannins, punicalagin (1) and isoterchebulin (2), along with eschweilenol C (3) and ellagic acid (4) were isolated from the bark of Terminalia bentzoë (L...
October 17, 2018: Fitoterapia
Maarten L De Mol, Nico Snoeck, Sofie L De Maeseneire, Wim K Soetaert
The struggle of humans versus pathogens is a never ending battle. Since the discovery of antibiotics humans have tipped the scales in their favour, but today bacteria are nullifying this advantage by developing resistance mechanisms against these molecules. The plethora of different antibiotics active against pathogens is shrinking while the discovery of new molecules is arduous. Especially the development of drugs active against Gram- pathogens continues slowly. New strategies to discover novel, potent antibiotics are hence needed...
October 17, 2018: Biotechnology Advances
Thomas F Baumert, Thomas Berg, Joseph K Lim, David R Nelson
Chronic infection with hepatitis C virus (HCV) is a major cause of liver disease and hepatocellular carcinoma worldwide. Following the discovery of HCV 3 decades ago, the identification of the structure of the viral proteins, combined with high-throughput replicon models, enabled the discovery and development of direct-acting antivirals. These agents have revolutionized care of patients, with cure rates of more than 90%. We review the status of direct-acting antiviral therapies for HCV infection and discuss remaining challenges...
October 17, 2018: Gastroenterology
O Olén, J Askling, M C Sachs, P Frumento, M Neovius, K E Smedby, A Ekbom, P Malmborg, J F Ludvigsson
BACKGROUND & AIMS: Childhood onset inflammatory bowel disease (IBD) is believed to be a more severe disease than adult-onset IBD, but there is little information on all-cause and cause-specific mortality in patients with childhood-onset IBD. We performed a population-based cohort study, with 50 years of follow up, to estimate absolute and relative risks for overall and cause-specific mortality in patients with childhood-onset IBD, during childhood and adulthood. METHODS: We identified children with a diagnosis of IBD (less than 18 years old) in the Swedish nationwide health registers (1964-2014; n=9442) and individuals from the general population matched for sex, age, calendar year, and place of residence (reference group; n=93,180)...
October 17, 2018: Gastroenterology
Anneleen Van Hout, Alex Klarenbeek, Vladimir Bobkov, Jordi Doijen, Marta Arimont, Chunxia Zhao, Raimond Heukers, Rebecca Rimkunas, Chris de Graaf, Theo Verrips, Bas van der Woning, Hans de Haard, Joseph B Rucker, Kurt Vermeire, Tracy Handel, Tom Van Loy, Martine J Smit, Dominique Schols
The chemokine receptor CXCR4 and its ligand CXCL12 contribute to a variety of human diseases, such as cancer. CXCR4 is also a major co-receptor facilitating HIV entry. Accordingly, CXCR4 is considered as an attractive therapeutic target. Drug side effects and poor pharmacokinetic properties have been major hurdles that have prevented the implementation of CXCR4-directed inhibitors in treatment regimes. We evaluated the activity of a new and promising class of biologics, namely CXCR4-targeting nanobodies, with the purpose of identifying nanobodies that would preferentially inhibit HIV infection, while minimally disturbing other CXCR4-related functions...
October 17, 2018: Biochemical Pharmacology
Mangesh Tiwaskar, Amit Langote, Resham Kashyap, Archana Toppo
Amlodipine is a classical drug with varied properties extending from control of blood pressure to as an antianginal and anti atherosclerotic agent. Amlodipine is a longer acting dihydropyridine calcium channel blocker, effective for 24 hours BP control and cause no BP variability. It is a powerful, well-tolerated, and safe antihypertensive agents that is widely used either alone or as a key component of combination therapy for hypertension. Its effective BP reduction has shown proven benefits in cardiovascular event reduction that is supported with strong evidences from large randomised controlled trials...
March 2018: Journal of the Association of Physicians of India
Samia Rebouh, Sonia Lefnaoui, Mounir Bouhedda, Madiha M Yahoum, Salah Hanini
In the present study, we investigated the drug release behavior from cellulose derivative (CD) matrices in the oral form of tablets. We used the adaptive neural-fuzzy inference system (ANFIS) to predict the best formulation parameters to get the perfect sustained drug delivery using ibuprofen (IB) as a model drug. The different formulations were prepared with different CDs, namely CMC, HEC, HPC, HPMC, and MC. The amount of the active ingredient varied between 20 and 50%. The flow properties of the powder mixtures were evaluated for their angle of repose, compressibility index, and Hausner ratio, while the tablets were evaluated for weight uniformity, hardness, friability, drug content, disintegration time, and release ratio...
October 19, 2018: Drug Delivery and Translational Research
Emma D Deeks
Doravirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by Merck & Co for the treatment of HIV-1 infection. The drug is approved in the USA both as a single-agent tablet (Pifeltro™) and as a fixed-dose combination tablet with the nucleos(t)ide reverse transcriptase inhibitors lamivudine and tenofovir disoproxil fumarate (Delstrigo™). Each formulation is indicated in the USA for treating HIV-1 infection in adults with no prior antiretroviral treatment, has received a positive opinion in the EU for treating HIV-1 infection in adults without resistance to NNRTIs or (in the case of the fixed-dose combination tablet) lamivudine or tenofovir, and is also under regulatory review for the treatment of HIV-1 infection in Canada...
October 19, 2018: Drugs
Hamid Dolatshad, Dharamveer Tatwavedi, Doaa Ahmed, Jana F Tegethoff, Jacqueline Boultwood, Andrea Pellagatti
Induced pluripotent stem cells (iPSCs) were first described over a decade ago and are currently used in various basic biology and clinical research fields. Recent advances in the field of human iPSCs have opened the way to a better understanding of the biology of human diseases. Disease-specific iPSCs provide an unparalleled opportunity to establish novel human cell-based disease models, with the potential to enhance our understanding of the molecular mechanisms underlying human malignancies, and to accelerate the identification of effective new drugs...
October 10, 2018: Advances in Biological Regulation
Valentin Ritschl, Angelika Lackner, Carina Boström, Erika Mosor, Michaela Lehner, Maisa Omara, Romualdo Ramos, Paul Studenic, Josef Sebastian Smolen, Tanja Alexandra Stamm
BACKGROUND: It is estimated that 50-70% of patients with rheumatoid arthritis (RA) are non-adherent to their recommended treatment. Non-adherent patients have a higher risk of not reaching an optimal clinical outcome. We explored factors associated with nonadherence from the patient's perspective. METHODS: Four hundred and fifty-nine RA patients (346 (75.4%) females; mean age 63.0 ± 14.8 years) who failed to attend follow-up visits in two rheumatology centres were eligible to participate in a qualitative interview study...
October 19, 2018: Arthritis Research & Therapy
Yujuan Zhan, Kun Wang, Qiao Li, Yidan Zou, Bonan Chen, Qing Gong, Hiuting Idy Ho, Ting Yin, Fangyuan Zhang, Yuhua Lu, Weijie Wu, Yilin Zhang, Yuhui Tan, Biaoyan Du, Xiaodong Liu, Jianyong Xiao
Chemoresistance is a major limiting factor that impairs the outcome of non-small cell lung cancer (NSCLC) chemotherapy. Paclitaxel (Tax) induces protective autophagy in NSCLC cells, leading to the development of drug resistance. We recently identified a new autophagy inhibitor (alpha-hederin) and hypothesized that it may promote the killing effect of Tax on NSCLC cells. We found that alpha-hederin (α-Hed) could block late autophagic flux in NSCLC cells by altering lysosomal pH and inhibiting lysosomal cathepsin D maturation...
October 18, 2018: International Journal of Molecular Sciences
Haibin Pan, Yuqian Yan, Jing Zhang, Shan Zhao, Liqiang Feng, Junxian Ou, Na Cao, Min Li, Wei Zhao, Chengsong Wan, Ashrafali M Ismail, Jaya Rajaiya, James Chodosh, Qiwei Zhang
In 1955, Human adenovirus type 14 (HAdV-B14p) was firstly identified in a military trainee diagnosed as acute respiratory disease (ARD) in the Netherlands. Fifty years later, a genomic variant, HAdV-B14p1, re-emerged in the U.S. and caused large and fatal ARD outbreaks. Subsequently, more and more ARD outbreaks occurred in Canada, the UK, Ireland, and China, in both military and civil settings. To generate a tool for the efficient characterization of this new genomic variant, a full-length infectious genomic clone of HAdV-B14 was successfully constructed using one-step Gibson Assembly method in this study...
October 18, 2018: Viruses
Vijay Mishra, Kuldeep K Bansal, Asit Verma, Nishika Yadav, Sourav Thakur, Kalvatala Sudhakar, Jessica M Rosenholm
Solid lipid nanoparticles (SLNs) are nanocarriers developed as substitute colloidal drug delivery systems parallel to liposomes, lipid emulsions, polymeric nanoparticles, and so forth. Owing to their unique size dependent properties and ability to incorporate drugs, SLNs present an opportunity to build up new therapeutic prototypes for drug delivery and targeting. SLNs hold great potential for attaining the goal of targeted and controlled drug delivery, which currently draws the interest of researchers worldwide...
October 18, 2018: Pharmaceutics
Romina Gabriela Armando, Diego Luis Mengual Gómez, Ezequiel Ivan Juritz, Pablo Lorenzano Menna, Daniel Eduardo Gomez
Immortality is one of the main features of cancer cells. Tumor cells have an unlimited replicative potential, principally due to the holoenzyme telomerase. Telomerase is composed mainly by dyskerin (DKC1), a catalytic retrotranscriptase (hTERT) and an RNA template (hTR). The aim of this work is to develop new inhibitors of telomerase, selecting the interaction between hTR⁻DKC1 as a target. We designed two models of the human protein DKC1: homology and ab initio. These models were evaluated by different procedures, revealing that the homology model parameters were the most accurate...
October 18, 2018: International Journal of Molecular Sciences
Barbara Rojek, Marek Wesolowski
A compatibility study of drug substance with excipients is a crucial step in the drug development process in order to generate potent final drug formulations for efficient and safe therapy for various diseases. Thus, the development of new methods for compatibility studies is a great challenge. For this reason, a new approach based on improvement of FTIR spectra and TG curves interpretation using factor analysis (FA) was developed as a screening technique for assessing the compatibility of acetazolamide with selected excipients...
October 13, 2018: Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy
Monika Mishra, Viney Chawla, Pooja Chawla
In order to optimize drug action, new drug formulations have been developed based upon the prodrug approach. This study was inspired by the increasing interest in the field of macromolecular prodrugs and Piroxicam maleate was used as a model drug. A total of five prodrugs were synthesized using beta cyclodextrin, chitosan, pectin, egg albumin, bovine serum albumin. The synthesized conjugates were characterized on the basis of UV, IR and NMR techniques. In-vitro hydrolysis studies were carried out at pH 1...
October 16, 2018: International Journal of Biological Macromolecules
Yixia Qian, Yuehua Wang, Fei Jia, Zihua Wang, Chunyan Yue, Weikai Zhang, Zhiyuan Hu, Weizhi Wang
Mild acidity matrix, rich blood vessels and special biomarkers constitute the primary tumor microenvironment. Nanoparticles could change their physicochemical characteristics by functionalizing a series of moieties which is responsive towards pH or specific markers. So precise regulation of nanocarrier-based drug delivery systems by the tumor microenvironment has showed great potential for theranostics. Herein, we developed a smart nano delivery system STD-NM, showing tumor microenvironment responsive targeting, efficient drug delivery and precise evaluation of therapeutic effect in vivo...
October 9, 2018: Biomaterials
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