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Drug Discovery Today

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https://www.readbyqxmd.com/read/29969684/human-pharmacological-approaches-to-trp-ion-channel-based-analgesic-drug-development
#1
REVIEW
Iris Weyer-Menkhoff, Jörn Lötsch
The discovery of novel analgesic drug targets is an active research topic owing to insufficient treatment options for persisting pain. Modulators of temperature-sensing transient receptor potential ion channels (thermoTRPs), in particular TRPV2, TRPV1, TRPM8 and TRPA1, have reached clinical development. This requires access for TRP channels and the effects of specific modulators in humans. This is currently possible via (i) the study of TRP channel function in human-derived cell lines, (ii) immunohistochemical visualization of TRP channel expression in human tissues, (iii) human experimental pain models employing sensitization by means of topical application of TRP channel activators including capsaicin (TRPV1), menthol (TRPM8), mustard oil and cinnamaldehyde (TRPA1), and (iv) the study of phenotypic consequences of human TRP gene variants...
June 30, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29964181/mapping-genes-for-drug-chronotherapy
#2
REVIEW
Kun Wei, Qian Wang, Jingwen Gan, Shilong Zhang, Meixia Ye, Claudia Gragnoli, Rongling Wu
Genome-wide association studies have been increasingly used to map and characterize genes that contribute to interindividual variation in drug response. Some studies have integrated the pharmacokinetic (PK) and pharmacodynamic (PD) processes of drug reactions into association mapping, gleaning new insight into how genes determine the dynamic relationship of drug effect and drug dose. Here, we present an evolutionary framework by which two distinct concepts, chronopharmacodynamics and heterochrony (describing variation in the timing and rate of developmental events), are married to comprehend the pharmacogenetic architecture of drug response...
June 28, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29958991/delivery-systems-of-local-anesthetics-in-bone-surgery-are-they-efficient-and-safe
#3
REVIEW
Manon Dupleichs, Qiman Gao, Zahi Badran, Pascal Janvier, Jean-Michel Bouler, Olivier Gauthier, Faleh Tamimi, Elise Verron
Management of postoperative pain following bone surgery includes administration of local anesthetics (LAs). Smart delivery systems, including triggered systems, have been designed to provide a continuous release of LA in situ. However, these systems can provide a high level of LA locally. This review will examine the state-of-the-art regarding the LA delivery systems optimized for management of postoperative pain in bone surgery and will discuss the potential adverse effects of LAs on the overall pathways of bone healing, including the inflammation response phase, hemostasis phase, tissue repair phase and remodeling phase...
June 26, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29953957/marketing-authorisation-applications-submitted-to-the-european-medicines-agency-by-small-and-medium-sized-enterprises-an-analysis-of-major-objections-and-their-impact-on-outcomes
#4
REVIEW
Nadia Amaouche, Hélène Casaert Salomé, Olivier Collignon, Mariana Roldao Santos, Constantinos Ziogas
Small and medium-sized enterprises (SMEs) are an important source of innovative medicines. Compared with their larger counterparts, they experience challenges as a result of insufficient human and financial resources that can hamper drug development and regulatory compliance. This analysis reviews the profile of major objections raised in applications for medicines for human use submitted by SMEs to the European Medicines Agency between 2011 and 2015 and their impact on the outcome of applications. It showed that SMEs experience challenges in the quality (e...
June 25, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29936248/u-biopred-evaluation-of-the-value-of-a-public-private-partnership-to-industry
#5
REVIEW
John H Riley, Veit J Erpenbeck, J G Matthews, C T J Holweg, C Compton, W Seibold, T Higenbottam, S S Wagers, A Rowe, D Myles
Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) was initiated in the first year of the Innovative Medicines Initiative (IMI). It was an ambitious plan to tackle the understanding of asthma through an integration of clinical and multi-'omics approaches that necessitated the bringing together of industry, academic, and patient representatives because it was too large to be managed by any one of the partners in isolation. It was a novel experience for all concerned. In this review, we describe the main features of the U-BIOPRED experience from the industry perspective...
June 21, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29936247/renovation-as-innovation-is-repurposing-the-future-of-drug-discovery-research
#6
EDITORIAL
Arthur Neuberger, Nektarios Oraiopoulos, Donald L Drakeman
No abstract text is available yet for this article.
June 21, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29936246/the-inherent-risks-associated-with-newly-traded-biopharmaceutical-firms
#7
REVIEW
David R Williams, Trent J Spaulding
Here, we provide a comprehensive study related to the risks of all biopharmaceutical firms going public in the USA between 1996 and 2015. We found 355 firms that met our requirements for being in the sector that focuses on creating drugs for humans. Collectively, these firms spent approximately US$86.9 billion on research and development (R&D) during this time. They also lost approximately US$69.3 billion in combined net income. We also examine the delisting of these firms from a public market, their number of collaborators at the initial public offering (IPO), and estimate the percentage ownership by other biopharmaceutical firms at the IPO...
June 21, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29936245/small-molecule-inhibitors-of-macrophage-migration-inhibitory-factor-mif-as-an-emerging-class-of-therapeutics-for-immune-disorders
#8
REVIEW
Tjie Kok, Anna A Wasiel, Robbert H Cool, Barbro N Melgert, Gerrit J Poelarends, Frank J Dekker
Macrophage migration inhibitory factor (MIF) is an important cytokine for which an increasing number of functions is being described in the pathogenesis of inflammation and cancer. Nevertheless, the availability of potent and druglike MIF inhibitors that are well-characterized in relevant disease models remains limited. Highly potent and selective small-molecule MIF inhibitors and validation of their use in relevant disease models will advance drug discovery. In this review, we provide an overview of recent advances in the identification of MIF as a pharmacological target in the pathogenesis of inflammatory diseases and cancer...
June 21, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29936244/neural-network-and-deep-learning-algorithms-used-in-qsar-studies-merits-and-drawbacks
#9
REVIEW
Fahimeh Ghasemi, Alireza Mehridehnavi, Alfonso Pérez-Garrido, Horacio Pérez-Sánchez
The past two decades are regarded as the golden age of using neural networks (NNs) in chemoinformatics. However, two major issues have arisen concerning their use: redundancy problems when dealing with small data sets, and the large number of compounds with thousands of descriptors, which gives rise to serious overfitting problems. Various NN algorithms, based on feature selection methods and learning algorithms, were devised to avoid these predicaments in drug discovery. Pruning the overfitting problem has emerged as another challenge in recent years, leading to the advent of deep-learning (DL) networks using innovative techniques...
June 21, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29935345/the-a-z-of-zika-drug-discovery
#10
REVIEW
Melina Mottin, Joyce V V B Borba, Rodolpho C Braga, Pedro H M Torres, Matheus C Martini, Jose Luiz Proenca-Modena, Carla C Judice, Fabio T M Costa, Sean Ekins, Alexander L Perryman, Carolina Horta Andrade
Despite the recent outbreak of Zika virus (ZIKV), there are still no approved treatments, and early-stage compounds are probably many years away from approval. A comprehensive A-Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery...
June 20, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29928850/importance-of-target-mediated-drug-disposition-for-small-molecules
#11
REVIEW
Dennis A Smith, Robert A B van Waterschoot, Neil J Parrott, Andrés Olivares-Morales, Thierry Lavé, Malcolm Rowland
Target concentration is typically not considered in drug discovery. However, if targets are expressed at relatively high concentrations and compounds have high affinity, such that most of the drug is bound to its target, in vitro screens can give unreliable information on compound affinity. In vivo, a similar situation will generate pharmacokinetic (PK) profiles that deviate greatly from those normally expected, owing to target binding affecting drug distribution and clearance. Such target-mediated drug disposition (TMDD) effects on small molecules have received little attention and might only become apparent during clinical trials, with the potential for data misinterpretation...
June 18, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29908266/human-specific-approaches-to-brain-research-for-the-21-st-century-a-south-american-perspective
#12
Marcia Triunfol, Stevens Rehen, Marina Simian, Troy Seidle
The 21 st century paradigm in toxicology, which emphasizes mechanistic understanding and species-relevant modeling of human biology and pathophysiology, is gaining traction in the wider biosciences through a global workshop series organized by the BioMed21 Collaboration. The second of this series, entitled Emerging Technology Toward Pathway-Based Human Brain Research, was held in Brazil in 2017, bringing together leading South American and international scientists, research funders and other stakeholders...
June 13, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29908265/retinal-pigment-epithelial-cells-as-a-therapeutic-tool-and-target-against-retinopathies
#13
REVIEW
Barbara Pavan, Alessandro Dalpiaz
Retinal pigment epithelium (RPE) is a cell monolayer essential for photoreceptor function and forming the blood-retinal barrier. RPE and retinal neurons share the same origin and a polarized cytoarchitecture. Several factors determine the phagocytosis and permeability of RPE, influencing photoreceptor renewal and drug delivery, efficacy and toxicity. Adult human RPE expresses neuronal markers in vitro, indicating a potential transdifferentiation. Degeneration of the RPE leads to death of photoreceptors and retinal neurons, resulting in the vision loss of retinopathy...
June 13, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29908264/connecting-the-pharmacogenetics-and-personalised-medicine-community
#14
EDITORIAL
Christine McNamee
No abstract text is available yet for this article.
June 13, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29906514/pragmatic-clinical-trials-ethical-imperatives-and-opportunities
#15
EDITORIAL
Shona Kalkman, Ghislaine J M W van Thiel, Diederick E Grobbee, Johannes J M van Delden
Pragmatic clinical trials generate robust real-world evidence that holds great potential to better inform decision making regarding new medicines. For clinicians, patients and regulators, this evidence would preferably be available sooner rather than later. This means that, ideally, market authorization of any given medicine is accompanied by evidence obtained from a pragmatic trial. Given the operational and regulatory complexities of pragmatic trials in general, stakeholders tend to be hesitant to employ more pragmatism at the time of market approval...
June 12, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29902520/drug-induced-rhabdomyolysis-atlas-dira-for-idiosyncratic-adverse-drug-reaction-management
#16
Zhining Wen, Yu Liang, Yingyi Hao, Brian Delavan, Ruili Huang, Mike Mikailov, Weida Tong, Menglong Li, Zhichao Liu
Drug-induced rhabdomyolysis (DIR) is an idiosyncratic and fatal adverse drug reaction (ADR) characterized in severe muscle injuries accompanied by multiple-organ failure. Limited knowledge regarding the pathophysiology of rhabdomyolysis is the main obstacle to developing early biomarkers and prevention strategies. Given the lack of a centralized data resource to curate, organize, and standardize widespread DIR information, here we present a Drug-Induced Rhabdomyolysis Atlas (DIRA) that provides DIR-related information, including: a classification scheme for DIR based on drug labeling information; postmarketing surveillance data of DIR; and DIR drug property information...
June 11, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29894812/why-are-there-no-drugs-indicated-for-sciatica-the-most-common-chronic-neuropathic-syndrome-of-all
#17
REVIEW
John D Markman, Ralf Baron, Jennifer S Gewandter
Here, we examine the stark contrast between the successes and failures of the clinical development of analgesics for different types of chronic low back pain (CLBP) syndrome over the past three decades. Multiple drugs with differing mechanisms of action have been developed for nonspecific axial-predominant low back syndromes and yet not a single therapy is indicated for any neuropathic low back pain syndrome (e.g., sciatica). Clinician findings have informed the entry criteria for neuropathic low back pain clinical trials, whereas entry criteria of axial CLBP trials have prioritized only patient reports of pain...
June 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29890228/interrogating-the-microbiome-experimental-and-computational-considerations-in-support-of-study-reproducibility
#18
REVIEW
Carine Poussin, Nicolas Sierro, Stéphanie Boué, James Battey, Elena Scotti, Vincenzo Belcastro, Manuel C Peitsch, Nikolai V Ivanov, Julia Hoeng
The microbiome is an important factor in human health and disease; and is investigated to develop novel therapeutics. Metagenomics leverages advances in sequencing technologies and computational analysis to identify and quantify the microorganisms present in a sample. This field has, however, not yet reached maturity and the international metagenomics community, aware of the current limitations and of the necessity for standardization, has started investigating sources of variability in experimental and computational workflows...
June 8, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29890227/therapeutic-application-of-antibody-fragments-in-autoimmune-diseases-current-state-and-prospects
#19
REVIEW
João C Fernandes
Over the past decades, conventional antibodies have been dissected through different strategies into smaller antigen-binding fragments. Therapeutic solutions built on such fragments can offer several advantages, including the capacity to access challenging epitopes, reduced immunogenicity, lower production costs, and higher stability. Although the development of antibody fragments for cancer therapy has received more attention than any other potential therapeutic application, the development of pharmacological tools based on these molecules for the treatment of autoimmune diseases (AIDs) has been growing at a fast pace...
June 8, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29890226/the-fruit-fly-drosophila-melanogaster-as-an-innovative-preclinical-adme-model-for-solute-carrier-membrane-transporters-with-consequences-for-pharmacology-and-drug-therapy
#20
REVIEW
Yiwen Wang, Bernard Moussian, Elke Schaeffeler, Matthias Schwab, Anne T Nies
Solute carrier membrane transporters (SLCs) control cell exposure to small-molecule drugs, thereby contributing to drug efficacy and failure and/or adverse effects. Moreover, SLCs are genetically linked to various diseases. Hence, in-depth knowledge of SLC function is fundamental for a better understanding of disease pathophysiology and the drug development process. Given that the model organism Drosophila melanogaster (fruit fly) expresses SLCs, such as for the excretion of endogenous and toxic compounds by the hindgut and Malpighian tubules, equivalent to human intestine and kidney, this system appears to be a promising preclinical model to use to study human SLCs...
June 8, 2018: Drug Discovery Today
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