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https://www.readbyqxmd.com/read/28748467/target-safety-assessment-strategies-and-resources
#1
Richard J Brennan
An in-depth evaluation of target safety is an invaluable resource throughout drug discovery and development. The goal of a target safety evaluation is to identify potential unintended adverse consequences of target modulation, and to propose a risk evaluation and mitigation strategy to shepherd compounds through the discovery and development pipeline, to confirm and characterize unavoidable on-target toxicities in a timely manner to assist in early program advancement decisions, and to anticipate, monitor, and manage potential clinical adverse events...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28747776/animal-models-of-%C3%AE-synucleinopathy-for-parkinson-disease-drug-development
#2
REVIEW
James B Koprich, Lorraine V Kalia, Jonathan M Brotchie
A major challenge in Parkinson disease (PD) will be to turn an emerging and expanding pipeline of novel disease-modifying candidate compounds into therapeutics. Novel targets need in vivo validation, and candidate therapeutics require appropriate preclinical platforms on which to define potential efficacy and target engagement before advancement to clinical development. We propose that α-synuclein (α-syn)-based mammalian models will be crucial for this process. Here, we review α-syn transgenic mouse models, viral vector models of α-syn overexpression and models of 'prion-like' spread of α-syn, and describe how each of these model types may contribute to PD drug discovery...
July 13, 2017: Nature Reviews. Neuroscience
https://www.readbyqxmd.com/read/28747660/4-dimensional-functional-profiling-in-the-convulsant-treated-larval-zebrafish-brain
#3
Matthew J Winter, Dylan Windell, Jeremy Metz, Peter Matthews, Joe Pinion, Jonathan T Brown, Malcolm J Hetheridge, Jonathan S Ball, Stewart F Owen, Will S Redfern, Julian Moger, Andrew D Randall, Charles R Tyler
Functional neuroimaging, using genetically-encoded Ca(2+) sensors in larval zebrafish, offers a powerful combination of high spatiotemporal resolution and higher vertebrate relevance for quantitative neuropharmacological profiling. Here we use zebrafish larvae with pan-neuronal expression of GCaMP6s, combined with light sheet microscopy and a novel image processing pipeline, for the 4D profiling of chemoconvulsant action in multiple brain regions. In untreated larvae, regions associated with autonomic functionality, sensory processing and stress-responsiveness, consistently exhibited elevated spontaneous activity...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28730958/engineering-synergistically-active-and-bioavailable-cost-effective-medicines-for-neglected-tropical-diseases-the-role-of-excipients
#4
Dolores R Serrano, Aikaterini Lalatsa, M Auxiliadora Dea-Ayuela
Leishmaniasis is a neglected tropical disease responsible for the ninth largest disease burden in the world threatening 350 million people mostly in developing countries. The lack of efficacy, severe adverse effects, long duration, high cost and parenteral administration of the current therapies result in poor patient compliance and emergence of resistance. Leishmaniasis' unmet need for safer, affordable and more effective treatments is only partly addressed by today's global health product pipeline that focuses on products amenable to rapid clinical development, mainly by reformulating or repurposing existing drugs for new uses...
July 19, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28723468/trends-in-antibiotic-resistance-in-urologic-practice
#5
REVIEW
Hala Kandil, Emma Cramp, Tejal Vaghela
CONTEXT: The significant global upsurge in antimicrobial resistance, particularly among Enterobacteriaceae, represents a serious threat to health care systems. The implications for urologic practice are of particular concern. OBJECTIVE: To review trends in antibiotic resistance in urologic practice. EVIDENCE ACQUISITION: We report current European trends of resistance in Gram-negative uropathogens. EVIDENCE SYNTHESIS: In addition to β-lactam resistance, Gram-negative pathogens are often resistant to multiple drug classes, including aminoglycosides, fluoroquinolones, and carbapenems, commonly used to treat urologic infections...
October 2016: European Urology Focus
https://www.readbyqxmd.com/read/28721339/the-role-of-glucagon-like-peptide-1-receptor-agonists-in-the-treatment-of-type-2-diabetes
#6
Erin St Onge, Shannon Miller, Elizabeth Clements, Lindsay Celauro, Ke'la Barnes
The role of GLP-1 agonists in the treatment of type 2 diabetes have been shown to be viable options for add-on therapy in diabetic patients, as well as potential monotherapy options. With six available GLP-1 agents, and new combination products in the pipeline, they are a promising drug class for type 2 diabetic patients, especially due to their extended dosing interval and potential weight loss benefits.
June 2017: Journal of Translational Internal Medicine
https://www.readbyqxmd.com/read/28720135/exploring-anti-malarial-potential-of-fda-approved-drugs-an-in-silico-approach
#7
Gayatri Ramakrishnan, Nagasuma Chandra, Narayanaswamy Srinivasan
BACKGROUND: The critically important issue on emergence of drug-resistant malarial parasites is compounded by cross resistance, where resistance to one drug confers resistance to other chemically similar drugs or those that share mode of action. This aspect requires discovery of new anti-malarial compounds or formulation of new combination therapy. The current study attempts to contribute towards accelerating anti-malarial drug development efforts, by exploring the potential of existing FDA-approved drugs to target proteins of Plasmodium falciparum...
July 18, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28717660/a-novel-molecular-diagnostics-platform-for-somatic-and-germline-precision-oncology
#8
Rubén Cabanillas, Marta Diñeiro, David Castillo, Patricia C Pruneda, Cristina Penas, Guadalupe A Cifuentes, Álvaro de Vicente, Noelia S Durán, Rebeca Álvarez, Gonzalo R Ordóñez, Juan Cadiñanos
BACKGROUND: Next-generation sequencing (NGS) opens new options in clinical oncology, from therapy selection to genetic counseling. However, realization of this potential not only requires succeeding in the bioinformatics and interpretation of the results, but also in their integration into the clinical practice. We have developed a novel NGS diagnostic platform aimed at detecting (1) somatic genomic alterations associated with the response to approved targeted cancer therapies and (2) germline mutations predisposing to hereditary malignancies...
July 2017: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/28716510/evaluation-of-in-vivo-and-in-vitro-models-of-toxicity-by-comparison-of-toxicogenomics-data-with-the-literature
#9
Katerina Taškova, Jean-Fred Fontaine, Ralf Mrowka, Miguel A Andrade-Navarro
Toxicity affecting humans is studied by observing the effects of chemical substances in animal organisms (in vivo) or in animal and human cultivated cell lines (in vitro). Toxicogenomics studies collect gene expression profiles and histopathology assessment data for hundreds of drugs and pollutants in standardized experimental designs using different model systems. These data are an invaluable source for analyzing genome-wide drug response in biological systems. However, a problem remains that is how to evaluate the suitability of heterogeneous in vitro and in vivo systems to model the many different aspects of human toxicity...
July 14, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28709570/systemic-therapies-in-atopic-dermatitis-the-pipeline
#10
Yael Renert-Yuval, Emma Guttman-Yassky
Atopic dermatitis (AD), the most prevalent inflammatory skin disease, is characterized by robust T-cell activation. The disease has several subtypes, all having a common T helper type 2 (Th2)/Th22 polarization, but it also displays differential immune skewing, such as increased Th17/interleukin 23 skewing in the skin of intrinsic, Asian, and early pediatric AD patients. Current systemic treatments for moderate to severe AD are largely unsatisfactory, associated with significant adverse effects and low compliance...
July 2017: Clinics in Dermatology
https://www.readbyqxmd.com/read/28708847/attitudes-and-perceptions-towards-novel-objective-measures-of-arv-based-vaginal-ring-use-results-from-a-global-stakeholder-survey
#11
Randy M Stalter, Jenae Tharaldson, Derek H Owen, Eunice Okumu, Thomas Moench, Natasha Mack, Elizabeth E Tolley, Kathleen M MacQueen
Results of recent microbicide and pre-exposure prophylaxis clinical trials have shown adherence to be a significant challenge with new HIV prevention technologies. As the vaginal ring containing dapivirine moves into two open label follow-on studies (HOPE/MTN-025 and DREAM) and other antiretroviral-based and multi-purpose prevention technology ring products advance through the development pipeline, there is a need for more accurate and reliable measures of adherence to microbicide ring products. We previously conducted a comprehensive landscape analysis to identify new technologies that could be applied to adherence measurement of vaginal rings containing antiretrovirals...
2017: PloS One
https://www.readbyqxmd.com/read/28694231/repurposing-ivacaftor-for-treatment-of-staphylococcus-aureus-infections
#12
Ritesh Thakare, Alok Kumar Singh, Swetarka Das, N Vasudevan, Gorakhnath R Jachak, D Srinivas Reddy, Arunava Dasgupta, Sidharth Chopra
Drug repurposing of non-antimicrobials is a novel method to augment a seriously depleted drug pipeline for targeting drug-resistant pathogens. This article highlights the potent antimicrobial activity of Ivacaftor against Staphylococcus aureus, including vancomycin- and other multidrug-resistant strains. The potent activity of Ivacaftor in vivo is also demonstrated in a murine neutropenic thigh infection model. Taken together, these results support the potential of Ivacaftor as an antimicrobial agent for the treatment of staphylococcal infections...
July 7, 2017: International Journal of Antimicrobial Agents
https://www.readbyqxmd.com/read/28692323/identifying-inhibitors-of-inflammation-a-novel-high-throughput-maldi-tof-screening-assay-for-salt-inducible-kinases-siks
#13
Rachel E Heap, Anthony G Hope, Lesley-Anne Pearson, Kathleen M S E Reyskens, Stuart P McElroy, C James Hastie, David W Porter, J Simon C Arthur, David W Gray, Matthias Trost
Matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF) mass spectrometry has become a promising alternative for high-throughput drug discovery as new instruments offer high speed, flexibility and sensitivity, and the ability to measure physiological substrates label free. Here we developed and applied high-throughput MALDI TOF mass spectrometry to identify inhibitors of the salt-inducible kinase (SIK) family, which are interesting drug targets in the field of inflammatory disease as they control production of the anti-inflammatory cytokine interleukin-10 (IL-10) in macrophages...
July 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28687337/a-translational-synthetic-biology-platform-for-rapid-access-to-gram-scale-quantities-of-novel-drug-like-molecules
#14
James Reed, Michael J Stephenson, Karel Miettinen, Bastiaan Brouwer, Aymeric Leveau, Paul Brett, Rebecca J M Goss, Alain Goossens, Maria A O'Connell, Anne Osbourn
Plants are an excellent source of drug leads. However availability is limited by access to source species, low abundance and recalcitrance to chemical synthesis. Although plant genomics is yielding a wealth of genes for natural product biosynthesis, the translation of this genetic information into small molecules for evaluation as drug leads represents a major bottleneck. For example, the yeast platform for artemisinic acid production is estimated to have taken >150 person years to develop. Here we demonstrate the power of plant transient transfection technology for rapid, scalable biosynthesis and isolation of triterpenes, one of the largest and most structurally diverse families of plant natural products...
July 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28683317/whole-body-profiling-of-cancer-metastasis-with-single-cell-resolution
#15
Shimpei I Kubota, Kei Takahashi, Jun Nishida, Yasuyuki Morishita, Shogo Ehata, Kazuki Tainaka, Kohei Miyazono, Hiroki R Ueda
Stochastic and proliferative events initiated from a single cell can disrupt homeostatic balance and lead to fatal disease processes such as cancer metastasis. To overcome metastasis, it is necessary to detect and quantify sparsely distributed metastatic cells throughout the body at early stages. Here, we demonstrate that clear, unobstructed brain/body imaging cocktails and computational analysis (CUBIC)-based cancer (CUBIC-cancer) analysis with a refractive index (RI)-optimized protocol enables comprehensive cancer cell profiling of the whole body and organs...
July 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28675044/delivery-of-chemotherapeutic-vcmmae-using-tobacco-mosaic-virus-nanoparticles
#16
Daniel L Kernan, Amy M Wen, Andrzej S Pitek, Nicole F Steinmetz
The first-line treatment for non-Hodgkin's lymphoma is chemotherapy. While generally well tolerated, off-target effects and chemotherapy-associated complications are still of concern. To overcome the challenges associated with systemic chemotherapy, we developed a biology-inspired, nanoparticle drug delivery system (nanoDDS) making use of the nucleoprotein components of the tobacco mosaic virus (TMV). Virus-based nanoparticles, including the high-aspect ratio soft nanorods formed by TMV, are growing in popularity as nanoDDS due to their simple genetic and chemical engineerability, size and shape tunability, and biocompatibility...
January 1, 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28669031/experimental-design-and-reporting-standards-for-metabolomics-studies-of-mammalian-cell-lines
#17
REVIEW
Sarah Hayton, Garth L Maker, Ian Mullaney, Robert D Trengove
Metabolomics is an analytical technique that investigates the small biochemical molecules present within a biological sample isolated from a plant, animal, or cultured cells. It can be an extremely powerful tool in elucidating the specific metabolic changes within a biological system in response to an environmental challenge such as disease, infection, drugs, or toxins. A historically difficult step in the metabolomics pipeline is in data interpretation to a meaningful biological context, for such high-variability biological samples and in untargeted metabolomics studies that are hypothesis-generating by design...
July 1, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28657400/a-review-of-radiation-countermeasures-focusing-on-injury-specific-medicinals-and-regulatory-approval-status-part-iii-countermeasures-under-early-stages-of-development-along-with-standard-of-care-medicinal-and-procedures-not-requiring-regulatory-approval-for
#18
Vijay K Singh, Briana K Hanlon, Paola T Santiago, Thomas M Seed
PURPOSE: Terrorist attacks, with their intent to maximize psychological and economic damage as well as inflicting sickness and death on given targeted populations, are an ever-growing worldwide concern in government and public sectors as they become more frequent, violent, and sensational. If given the chance, it is likely that terrorists will use radiological or nuclear weapons. To thwart these sinister efforts, both physical and medical countermeasures against these weapons are currently being researched and developed so that they can be utilized by the first responders, military, and medical providers alike...
June 28, 2017: International Journal of Radiation Biology
https://www.readbyqxmd.com/read/28654200/preparation-and-evaluation-of-potent-pentafluorosulfanyl-substituted-anti-tuberculosis-compounds
#19
Garrett C Moraski, Ryan Bristol, Natalie Seeger, Helena I Boshoff, Patricia Siu-Yee Tsang, Marvin J Miller
The global fight to stop tuberculosis (TB) remains a great challenge, particularly with the increase in drug-resistant strains and a lack of funding to support the development of new treatments. To bolster a precarious drug pipeline, we prepared a focused panel of eight pentafluorosulfanyl (SF5 ) compounds which were screened for their activity against Mycobacterium tuberculosis (Mtb) H37Rv in three different assay conditions and media. All eight compounds had sub-micromolar potency, and four displayed MICs <100 nm...
June 27, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28647378/leishmaniasis-drug-discovery-recent-progress-and-challenges-in-assay-development
#20
REVIEW
Bilal Zulfiqar, Todd B Shelper, Vicky M Avery
Leishmaniasis, caused by the trypanosomatid protozoan Leishmania, is endemic in 98 countries worldwide, with morbidity and mortality increasing daily. Despite available drugs, leishmaniasis faces the challenge of emerging resistance and toxicity concerns for current drug regimes. Identification of anti-leishmanial compounds representing new chemistry and novel mechanisms of action is essential to populate the drug discovery pipeline. The in vitro assays currently available have shown poor translational outcomes, with high compound attrition rates...
June 21, 2017: Drug Discovery Today
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