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Drug Discovery Today

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https://www.readbyqxmd.com/read/27919806/are-placebo-and-drug-specific-effects-additive-questioning-basic-assumptions-of-double-blinded-randomized-clinical-trials-and-presenting-novel-study-designs
#1
REVIEW
Tobias Kube, Winfried Rief
Double-blinded randomized clinical trials (RCTs) assume that pharmacological interventions have drug-specific and unspecific components. Traditional RCTs postulate an additivity of these two components. In this review, we provide evidence from both clinical trials and experimental studies that questions this 'additive model'. Given that the evaluation of drug treatments in RCTs is based on the assumption of additivity, its violation has far-reaching consequences. Therefore, we discuss an interactive model that, in contrast to the additive model, considers interactions between placebo and drug-specific effects...
December 2, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27919805/uplc-ms-for-metabolomics-a-giant-step-forward-in-support-of-pharmaceutical-research
#2
REVIEW
Ala F Nassar, Terence Wu, Samuel F Nassar, Adam V Wisnewski
Metabolomics is a relatively new and rapidly growing area of post-genomic biological research. As use of metabolomics technology grows throughout the spectrum of drug discovery and development, and its applications broaden, its impact is expanding dramatically. This review seeks to provide the reader with a brief history of the development of metabolomics, its significance and strategies for conducting metabolomics studies. The most widely used analytical tools for metabolomics: NMR, LC-MS and GC-MS, are discussed along with considerations for their use...
December 2, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27916639/binding-thermodynamics-discriminates-fragments-from-druglike-compounds-a-thermodynamic-description-of-fragment-based-drug-discovery
#3
Glyn Williams, György G Ferenczy, Johan Ulander, György M Keserű
Small is beautiful-reducing the size and complexity of chemical starting points for drug design allows better sampling of chemical space, reveals the most energetically important interactions within protein-binding sites and can lead to improvements in the physicochemical properties of the final drug. The impact of fragment-based drug discovery (FBDD) on recent drug discovery projects and our improved knowledge of the structural and thermodynamic details of ligand binding has prompted us to explore the relationships between ligand-binding thermodynamics and FBDD...
December 1, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27903430/minimizing-the-risk-of-chemically-reactive-metabolite-formation-of-new-drug-candidates-implications-for-preclinical-drug-design
#4
Andreas Brink, Axel Pähler, Christoph Funk, Franz Schuler, Simone Schadt
Many pharmaceutical companies aim to reduce reactive metabolite formation by chemical modification at early stages of drug discovery. A practice often applied is the detection of stable trapping products of electrophilic intermediates with nucleophilic trapping reagents to guide rational structure-based drug design. This contribution delineates this strategy to minimize the potential for reactive metabolite formation of clinical candidates during preclinical drug optimization, exemplified by the experience at Roche over the past decade...
November 27, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27894931/the-unique-status-of-first-in-human-studies-strengthening-the-social-value-requirement
#5
Michelle G J L Habets, Johannes J M van Delden, Annelien L Bredenoord
For clinical research to be ethical, risks need to be balanced by anticipated benefits. This is challenging for first-in-human (FIH) studies as participants are not expected to benefit directly, and risks are potentially high. We argue that this differentiates FIH studies from other clinical trials to the extent that they should be given unique status in international research ethics guidelines. As there is a general positive attitude regarding the benefits of science, it is important to establish a more systematic method to assess anticipated social value to safeguard participants not only from enrolling in risky, but also in futile trials...
November 25, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27890821/molecular-dynamics-driven-drug-discovery-leaping-forward-with-confidence
#6
REVIEW
Aravindhan Ganesan, Michelle L Coote, Khaled Barakat
Given the significant time and financial costs of developing a commercial drug, it remains important to constantly reform the drug discovery pipeline with novel technologies that can narrow the candidates down to the most promising lead compounds for clinical testing. The past decade has witnessed tremendous growth in computational capabilities that enable in silico approaches to expedite drug discovery processes. Molecular dynamics (MD) has become a particularly important tool in drug design and discovery...
November 24, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27890820/recent-developments-in-natural-product-based-drug-discovery-for-tuberculosis
#7
REVIEW
Maryline Dong, Bernhard Pfeiffer, Karl-Heinz Altmann
Natural products (NPs) have been at the origin of several established drugs against tuberculosis (TB). Although the current clinical TB pipeline does not feature any candidates derived from new NP scaffolds, numerous novel NP or NP analogs have been discovered in the recent past with promising activity against Mycobacterium tuberculosis (Mtb) This includes newly discovered structures as well as known NP classes that had not been previously recognized to be active against Mtb. These compounds could help to replenish the dry clinical TB pipeline and, thus, contribute to improvements in the treatment of a devastating disease...
November 24, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27890671/target-based-approaches-for-the-discovery-of-new-antimycobacterial-drugs
#8
REVIEW
Chiara Borsari, Stefania Ferrari, A Venturelli, Maria Paola Costi
Tuberculosis (TB) is a major global health problem and control of the disease is hampered by the increasing emergence of multidrug resistance (MDR) strains. Novel drugs are urgently needed to overcome this drug resistance. Among the most relevant targets of the past 3 years, here we consider nine enzymes that have been studied in a target-based approach. These targets are involved mainly in the biosynthesis of the cell wall, α-glucan, coenzyme A and acyl carrier protein precursor, and in energy production, DNA metabolism, and pyrimidine synthesis...
November 23, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27890670/updating-molecular-properties-during-early-drug-discovery
#9
Giulia Caron, Giuseppe Ermondi
Current multiparameter optimization (MPO) strategies make use of few experimental physicochemical descriptors (i.e., solubility at physiological pH and lipophilicity in the octanol/water system). Here, we show how new trends in drug discovery (i.e., large and flexible molecules for 'difficult' targets) call for the integration of ad hoc descriptors in MPO approaches. In particular, to rank, select, and optimize drug candidates, it could be relevant to have experimental data relating to the acid-base properties and the folding of the molecule to mask polar groups (so-called 'chameleonic' properties)...
November 23, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27890669/doxorubicin-nanotechnological-overviews-from-bench-to-bedside
#10
REVIEW
Maximiliano Cagel, Estefanía Grotz, Ezequiel Bernabeu, Marcela A Moretton, Diego A Chiappetta
Doxorubicin (DOX) is considered one of the most effective chemotherapeutic agents, used as a first-line drug in numerous types of cancer. Nevertheless, it exhibits serious adverse effects, such as lethal cardiotoxicity and dose-limiting myelosuppression. In this review, we focus on the description and the clinical benefits of different DOX-loaded nanotechnological platforms, not only those commercially available but also the ones that are currently in clinical phases, such as liposomes, polymeric nanoparticles, polymer-drug conjugates, polymeric micelles and ligand-based DOX-loaded nanoformulations...
November 23, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27890668/the-next-generation-of-antimicrobial-peptides-amps-as-molecular-therapeutic-tools-for-the-treatment-of-diseases-with-social-and-economic-impacts
#11
REVIEW
Nicolau B da Cunha, Nicole B Cobacho, Juliane F C Viana, Loiane A Lima, Kamila B O Sampaio, Stephan S M Dohms, Arthur C R Ferreira, César de la Fuente-Núñez, Fabrício F Costa, Octávio L Franco, Simoni C Dias
Anti-infective drugs have had a key role in the contemporary world, contributing to dramatically decrease mortality rates caused by infectious diseases worldwide. Antimicrobial peptides (AMPs) are multifunctional effectors of the innate immune system of mucosal surfaces and present antimicrobial activity against a range of pathogenic viruses, bacteria, and fungi. However, the discovery and development of new antibacterial drugs is a crucial step to overcome the great challenge posed by the emergence of antibiotic resistance...
November 23, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27888140/designed-covalent-allosteric-modulators-an-emerging-paradigm-in-drug-discovery
#12
REVIEW
Shaoyong Lu, Jian Zhang
Covalent allosteric modulators possess the pharmacological advantages (high potency, extended duration of action and low drug resistance) of covalent ligands and the additional benefit of the higher specificity and lower toxicity of allosteric modulators. This approach is gaining increasing recognition as a valuable tool in drug discovery. Here, we review the recent advances in the design of covalent allosteric modulators with an emphasis on successful examples. A broad spectrum of protein targets capable of being modulated by them reflects the prevalence of this strategy...
November 22, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27884746/collaborative-drug-discovery-for-more-medicines-for-tuberculosis-mm4tb
#13
REVIEW
Sean Ekins, Anna Coulon Spektor, Alex M Clark, Krishna Dole, Barry A Bunin
Neglected disease drug discovery is generally poorly funded compared with major diseases and hence there is an increasing focus on collaboration and precompetitive efforts such as public-private partnerships (PPPs). The More Medicines for Tuberculosis (MM4TB) project is one such collaboration funded by the EU with the goal of discovering new drugs for tuberculosis. Collaborative Drug Discovery has provided a commercial web-based platform called CDD Vault which is a hosted collaborative solution for securely sharing diverse chemistry and biology data...
November 22, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27871942/computational-approaches-for-modeling-and-analysis-of-human-on-chip-systems-for-drug-testing-and-characterization
#14
EDITORIAL
Mahadevabharath R Somayaji, Debarun Das, Andrzej Przekwas
No abstract text is available yet for this article.
November 18, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27871941/mimicking-the-ocular-environment-for-the-study-of-inflammatory-posterior-eye-disorders
#15
REVIEW
Nabeela K Dulull, Thilini R Thrimawithana, Faith A A Kwa
The common inflammatory posterior eye disorders, age-related degeneration and glaucoma often lead to irreversible vision loss. Current treatments do not target early stages or prevent disease progression. Consequently, the identification of biomarkers or early disease models that can accurately mimic the pathological processes involved is essential. Although none of the existing models can recapitulate all pathological aspects of these disorders, these models have revealed new therapeutic targets. Efforts to accurately phenotype eye disorders at various disease stages are warranted to generate a 'super' model that can replicate the microenvironment of the eye and associated pathological hallmarks effectively...
November 18, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27867084/new-concepts-in-asthma-clinical-phenotypes-and-pathophysiological-mechanisms
#16
REVIEW
Andreas R Koczulla, Claus F Vogelmeier, Holger Garn, Harald Renz
Asthma is among the most common chronic inflammatory diseases worldwide. Recent evidence indicates that the pathogenesis shows a high degree of heterogeneity. Patient subsets have been identified that exhibit different cellular and molecular patterns of dysregulation. A prominent example is eosinophilic Th2-driven asthma. These unique and molecular patterns are termed endotypes. Characterization of endotypes has broad implications for therapeutic interventions. Although ∼80% of asthmatic patients respond well to standard anti-inflammatory therapies, the remaining subset particularly consisting of severe patients requires a more specialized endotype-specific approach...
November 17, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27866010/the-botanical-explorer-s-legacy-a-promising-bioprospecting-tool
#17
Axel Helmstädter
Records about the traditional uses of medicinal plants can be considered useful in bioprospecting (i.e., the search for new active agents or lead structures in nature). Several sources like Egyptian papyri, early modern herbals and pharmacopoeias have been studied in this respect. It is proposed to use recordings of botanically interested explorers of the 19th and early 20th centuries as well. Some of them give detailed information about traditionally used medicinal plants and analysis shows that a considerable number of these have never been scientifically investigated...
November 16, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27866009/commercialisation-of-car-t-cell-therapies-business-model-spectrum
#18
EDITORIAL
Nafees N Malik, Matthew B Durdy
No abstract text is available yet for this article.
November 16, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27866008/organs-on-chips-research-and-commercial-perspectives
#19
REVIEW
Aarathi Balijepalli, Vaibhav Sivaramakrishan
Traditional preclinical drug testing methods utilize animal models to predict pharmacology and toxicology profiles. However, the data obtained from such methods cannot be directly extrapolated to humans and often do not provide a safe starting dose for first-in-human studies. To overcome these limitations, researchers have developed organs-on-chips - microfluidic devices that can mimic the cellular architecture and physiology more accurately than conventional methods. Because accurate organ-level interactions can be achieved with these devices, they have the potential to provide a realistic determination of a drug's pharmacokinetics, pharmacodynamics and toxicity profile...
November 16, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27866007/continuous-manufacturing-via-hot-melt-extrusion-and-scale-up-regulatory-matters
#20
REVIEW
Mohammed Maniruzzaman, Ali Nokhodchi
Currently, because globalization, the pharmaceutical industry is facing enormous challenges to comply with regulatory matters. Reduced patent life and overall decreased profitability of newly discovered drugs are also forcing the pharmaceutical industry to shorten the drug development time with maximum throughput. Therefore, continuous manufacturing (CM) processes via hot melt extrusion (HME) can be a promising alternative for achieving these goals. HME offers solvent-free green technology with a process that is easy to scale up...
November 16, 2016: Drug Discovery Today
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