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"Drug development"

Klaus Rose, Jane M Grant-Kels
Importance-Pediatric melanoma occurs, albeit rarely. Should patients be treated by today's medical standards, or be subjected to medically unnecessary clinical studies? Observations-We identified international, industry-sponsored pediatric melanoma studies triggered by regulatory demands in and further pediatric melanoma studies demanded by European Union pediatric investigation plans. We retrieved related regulatory documents from the internet. We analyzed these studies for rationale and medical beneficence on the basis of physiology, pediatric clinical pharmacology and rationale...
March 20, 2018: Children
Benoit Souchet, Mickael Audrain, Baptiste Billoir, Laurent Lecanu, Satoru Tada, Jérôme Braudeau
No abstract text is available yet for this article.
February 2018: Neural Regeneration Research
Margaret R Caplan, Eric S Daar, Katya C Corado
Treatment options for patients with HIV-1 infection have grown over the past two decades to include multiple fixed-dose combination pharmacotherapies that have greatly simplified administration of antiretroviral therapy (ART) for both patients and providers. Effective virologic control can often be achieved with once-daily use of a single-tablet regimen. Over the past three years, ART drug development has focused on the next generation of fixed-dose combinations for initial and maintenance therapy with improved efficacy, safety and tolerability...
March 20, 2018: Expert Opinion on Pharmacotherapy
Shi Hua Tan, Lei Ye
Cardiomyocytes derived from human pluripotent stem cells (hPSCs) are emerging as an invaluable alternative to primarily sourced cardiomyocytes. The potentially unlimited number of hPSC-derived cardiomyocytes (hPSC-CMs) that may be obtained in vitro facilitates high-throughput applications like cell transplantation for myocardial repair, cardiotoxicity testing during drug development, and patient-specific disease modeling. Despite promising progress in these areas, a major disadvantage that limits the use of hPSC-CMs is their immaturity...
March 19, 2018: Journal of Cardiovascular Translational Research
Marnix H Medema
Microbial and plant specialized metabolites, also known as natural products, are key mediators of microbe-microbe and host-microbe interactions and constitute a rich resource for drug development. In the past decade, genome mining has emerged as a prominent strategy for natural product discovery. Initially, such mining was performed on the basis of individual microbial genome sequences. Now, these efforts are being scaled up to fully genome-sequenced strain collections, pangenomes of bacterial genera, and large sets of metagenome-assembled genomes from microbial communities...
March 2018: MSystems
Daiju Yamazaki, Takashi Kitaguchi, Masakazu Ishimura, Tomohiko Taniguchi, Atsuhiro Yamanishi, Daisuke Saji, Etsushi Takahashi, Masao Oguchi, Yuta Moriyama, Sanae Maeda, Kaori Miyamoto, Kaoru Morimura, Hiroki Ohnaka, Hiroyuki Tashibu, Yuko Sekino, Norimasa Miyamoto, Yasunari Kanda
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to become a useful tool for proarrhythmia risk prediction in the non-clinical drug development phase. Several features including electrophysiological properties, ion channel expression profile and drug responses were investigated using commercially available hiPSC-CMs, such as iCell-CMs and Cor.4U-CMs. Although drug-induced arrhythmia has been extensively examined by microelectrode array (MEA) assays in iCell-CMs, it has not been fully understood an availability of Cor...
March 3, 2018: Journal of Pharmacological Sciences
Gary D Novack
Because of the epidemic of myopia with both its short-term and long-term effects, we desperately need ways to slow myopic progression. In this study which was part of a myopia prevention symposium, the author answers the following question: Assuming that researchers did come up with a pharmacological treatment to slow myopic progression-what would it take to obtain regulatory approval from the United States Food and Drug Administration (FDA)? Previous publicly available information (a 2003 FDA advisory committee on this topic, International Conference on Harmonisation guidances on drug development, and published articles) as well as the author's experience is used...
March 16, 2018: Eye & Contact Lens
Hao-Hsiang Hsu, John-Kevin Kracht, Laura Elisabeth Harder, Kerstin Rudnik, Gerd Lindner, Katharina Schimek, Uwe Marx, Ralf Pörtner
In vitro cultivated skin models have become increasingly relevant for pharmaceutical and cosmetic applications, and are also used in drug development as well as substance testing. These models are mostly cultivated in membrane-insert systems, their permeability toward different substances being an essential factor. Typically, applied methods for determination of these parameters usually require large sample sizes (e.g., Franz diffusion cell) or laborious equipment (e.g., fluorescence recovery after photobleaching (FRAP))...
February 23, 2018: Journal of Visualized Experiments: JoVE
Sandra Claes, Thomas D'huys, Anneleen Van Hout, Dominique Schols, Tom Van Loy
G protein-coupled receptors (GPCRs) are of great importance to the pharmaceutical industry as they are involved in many human diseases and include well-validated targets for therapeutic intervention. Discovery of lead compounds, including small synthetic molecules, that specifically inhibit the receptor's function, is an important initial step in drug development and relies on sensitive, specific, and robust cell-based assays. Here, we describe a kinetic cellular assay with a fluorescent readout primarily designed to identify receptor-specific antagonists that inhibit the intracellular Ca2+ release evoked upon the activation of the CXC chemokine receptor 4 (CXCR4) by its endogenous ligand, the CXC chemokine ligand 12 (CXCL12)...
February 20, 2018: Journal of Visualized Experiments: JoVE
Fumika Ichino, Hidemasa Bono, Takeru Nakazato, Atsushi Toyoda, Asao Fujiyama, Kikuo Iwabuchi, Ryoichi Sato, Hiroko Tabunoki
Human intestinal absorption is estimated using a human colon carcinoma cell line (Caco-2) cells from human colorectal adenocarcinoma, intestinal perfusion, or a mammalian model. These current evaluation systems are limited in their ability to estimate human intestinal absorption. In addition, in vivo evaluation systems using laboratory animals such as mice and rats entail animal ethics problems, and it is difficult to screen compounds on a large scale at the drug discovery stage. Thus, we propose the use of Bombyx mori larvae for evaluation of intestinal absorption of compounds as an alternative system in this study...
2018: Drug Discoveries & Therapeutics
Rinat Sultanov, Olga Lebedeva, Georgij Arapidi, Maria Lagarkova, Sergei Kiselev
The genetic reprogramming technology allows generation of induced pluripotent stem cells (iPSCs) from somatic cells (Takahashi and Yamanaka, 2006) [1]. iPSCs have the ability to self-renew, and to differentiate into any type of somatic cells, and are considered as a promising tool for drug development, disease modeling, and regenerative medicine. The reprogramming factors (oct4, sox2, klf4, c-myc) can be delivered to the cell nucleus either by vectors integrating into the genome (lentiviruses, retroviruses) or by non-integrative methods (e...
April 2018: Data in Brief
Sanna Rauhamäki, Pekka A Postila, Sanna Niinivehmas, Sami Kortet, Emmi Schildt, Mira Pasanen, Elangovan Manivannan, Mira Ahinko, Pasi Koskimies, Niina Nyberg, Pasi Huuskonen, Elina Multamäki, Markku Pasanen, Risto O Juvonen, Hannu Raunio, Juhani Huuskonen, Olli T Pentikäinen
Monoamine oxidase B (MAO-B) catalyzes deamination of monoamines such as neurotransmitters dopamine and norepinephrine. Accordingly, small-molecule MAO-B inhibitors potentially alleviate the symptoms of dopamine-linked neuropathologies such as depression or Parkinson's disease. Coumarin with a functionalized 3-phenyl ring system is a promising scaffold for building potent MAO-B inhibitors. Here, a vast set of 3-phenylcoumarin derivatives was designed using virtual combinatorial chemistry or rationally de novo and synthesized using microwave chemistry...
2018: Frontiers in Chemistry
Rupert Page, Rohit Shankar, Brendan N McLean, Jane Hanna, Craig Newman
Epilepsy is associated with a significant increase in morbidity and mortality. The likelihood is significantly greater for those patients with specific risk factors. Identifying those at greatest risk of injury and providing expert management from the earliest opportunity is made more challenging by the circumstances in which many such patients present. Despite increasing recognition of the importance of earlier identification of those at risk, there is little or no improvement in outcomes over more than 30 years...
2018: Frontiers in Neurology
John F Brothers, Matthew Ung, Renan Escalante-Chong, Jermaine Ross, Jenny Zhang, Yoonjeong Cha, Andrew Lysaght, Jason Funt, Rebecca Kusko
The tremendous expansion of data analytics and public and private big datasets presents an important opportunity for pre-clinical drug discovery and development. In the field of life sciences, the growth of genetic, genomic, transcriptomic and proteomic data is partly driven by a rapid decline in experimental costs as biotechnology improves throughput, scalability, and speed. Yet far too many researchers tend to underestimate the challenges and consequences involving data integrity and quality standards. Given the effect of data integrity on scientific interpretation, these issues have significant implications during preclinical drug development...
March 15, 2018: Biochemical Pharmacology
Hari S Misra, Ganesh K Maurya, Reema Chaudhary, Chitra S Misra
Cell division and genome segregation are mutually interdependent processes, which are tightly linked with bacterial multiplication. Mechanisms underlying cell division and the cellular machinery involved are largely conserved across bacteria. Segregation of genome elements on the other hand, follows different pathways depending upon its type and the functional components encoded on these elements. Small molecules, that are known to inhibit cell division and/or resolution of intertwined circular chromosome and maintenace of DNA topology have earlier been tested as antibacterial agents...
March 2018: Microbiological Research
Bryan Ceronie, Benjamin M Jacobs, David Baker, Nicolas Dubuisson, Zhifeng Mao, Francesca Ammoscato, Helen Lock, Hilary J Longhurst, Gavin Giovannoni, Klaus Schmierer
BACKGROUND: The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown. OBJECTIVE: To determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells. METHODS: A cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine...
March 17, 2018: Journal of Neurology
Nazia Karsan, Eric B Gonzales, Gregory Dussor
Acid-sensing ion channels (ASICs) are a family of ion channels, consisting of four members; ASIC1 to 4. These channels are sensitive to changes in pH and are expressed throughout the central and peripheral nervous systems-including brain, spinal cord, and sensory ganglia. They have been implicated in a number of neurological conditions such as stroke and cerebral ischemia, traumatic brain injury, and epilepsy, and more recently in migraine. Their expression within areas of interest in the brain in migraine, such as the hypothalamus and PAG, their demonstrated involvement in preclinical models of meningeal afferent signaling, and their role in cortical spreading depression (the electrophysiological correlate of migraine aura), has enhanced research interest into these channels as potential therapeutic targets in migraine...
March 16, 2018: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Christian Greunke, Elke Regina Duell, Paul Michael D'Agostino, Anna Glöckle, Katharina Lamm, Tobias Alexander Marius Gulder
Specialized metabolites from bacteria are an important source of inspiration for drug development. The genes required for the biosynthesis of such metabolites in bacteria are usually organized in so-called biosynthetic gene clusters (BGCs). Using modern bioinformatic tools, the wealth of genomic data can be scanned for such BGCs and the expected products can often structurally be predicted in silico. This facilitates the directed discovery of putatively novel bacterial metabolites. However, the production of these molecules often requires genetic manipulation of the BGC for activation or the expression of the pathway in a heterologous host...
March 13, 2018: Metabolic Engineering
Mousumi Pal, Utpal Nandi, Debaraj Mukherjee
Ruthenium (Ru) complexes are known for their promising anticancer activity presumably due to octahedral coordination geometry, slow ligand exchange rate, the range of different oxidation states and target specificity. This review article summarizes the physicochemical processes which are responsible for the selectivity of Ru complexes toward cancer cells over the normal cells. Emphasis has been given on the activation mechanism of Ru(III) complex administered as a prodrug and then the release of active species in an acidic environment of cancer cell through normal or photo induced hydrolysis or ligand oxidation...
March 7, 2018: European Journal of Medicinal Chemistry
David Bonnel, Raphaël Legouffe, André H Eriksson, Rasmus W Mortensen, Fabien Pamelard, Jonathan Stauber, Kim T Nielsen
Generation of skin distribution profiles and reliable determination of drug molecule concentration in the target region are crucial during the development process of topical products for treatment of skin diseases like psoriasis and atopic dermatitis. Imaging techniques like mass spectrometric imaging (MSI) offer sufficient spatial resolution to generate meaningful distribution profiles of a drug molecule across a skin section. In this study, we use matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to generate quantitative skin distribution profiles based on tissue extinction coefficient (TEC) determinations of four different molecules in cross sections of human skin explants after topical administration...
March 15, 2018: Analytical and Bioanalytical Chemistry
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