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"Drug development"

Elisa Luzon, Kevin Blake, Susan Cole, Anna Nordmark, Carolien Versantvoort, Eva Gil Berglund
Physiologically-Based Pharmacokinetic (PBPK) modelling is a valuable tool in drug development and regulatory assessment, as it offers the opportunity to simulate the pharmacokinetics of a compound, with a mechanistic understanding, in a variety of populations and situations. This work reviews the use and impact of such modelling in selected regulatory procedures submitted to the European Medicines Agency (EMA) before the end of 2015, together with its subsequent reflection in public documents relating to the assessment of these procedures...
October 22, 2016: Clinical Pharmacology and Therapeutics
Junsik Park, Minsuk Kwon, Eui-Cheol Shin
During immune responses antigen-specific T cells are regulated by several mechanisms, including through inhibitory receptors and regulatory T cells, to avoid excessive or persistent immune responses. These regulatory mechanisms, which are called 'immune checkpoints', suppress T cell responses, particularly in patients with chronic viral infections and cancer where viral antigens or tumor antigens persist for a long time and contribute to T cell exhaustion. Among these regulatory mechanisms, cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1) are the most well-known receptors and both have been targeted for drug development...
October 21, 2016: Archives of Pharmacal Research
Lufeng Zhang, Haiyan Qin, Wanwan Cui, Yang Zhou, Jianxiu Du
The development of new detection methods for proteases activity assay is important in clinical diagnostics and drug development. In this work, a simple, label-free, and turn-on fluorescent sensor was fabricated for trypsin, a protease produced in the pancreas. Cytochrome c, a natural substance of trypsin, could be selectively cleaved by trypsin into heme-peptide fragment. The produced heme-peptide fragment exhibited an intensive catalytic role on the H2O2-mediated the oxidation of thiamine to form strong fluorescent thiochrome...
December 1, 2016: Talanta
Md Forhad Hossain, Bashudeb Talukder, Mohammad Nasiruddin Rana, Refat Tasnim, Tanzina Sharmin Nipun, S M Naim Uddin, S M Moazzem Hossen
BACKGROUND: This plant is very popular ingredient of local made drinks during hot summer. After drinking this drink people feels fresh, relaxed and can enjoy sound sleep. Present study was aimed to assess the sedative properties of a plant Sterculia villosa leaves. Therefore, we tried to find out the methanolic extract from the leaves of Sterculia villosa leaves having any sedative activity or not. METHODS: The extract were subjected to various in vivo methods like hole cross test, open field test, elevated plus-maze (EPM) test, thiopental sodium induced sleeping time test...
October 21, 2016: BMC Complementary and Alternative Medicine
Elena S Don, Alexandra G Emelyanova, Natalia N Yakovleva, Nataliia V Petrova, Marina V Nikiforova, Evgeniy A Gorbunov, Sergey A Tarasov, Sergey G Morozov, Oleg I Epstein
The assessment of dose-response is an essential part of drug development in terms of the determination of a drug's effective dose, finding the safety endpoint, estimation of the pharmacokinetic profile and even validation of drug activity, especially for therapeutic agents with a principally novel mechanism of action. Drugs based on released-active forms of antibodies are a good example of such a target. In this study, the efficacy of the antiviral drug Anaferon for children (released-active form of antibodies to interferon-gamma) was tested in a dose-dependent manner (at doses of 0...
October 21, 2016: Journal of Medical Virology
Stacey Bagby, Wells A Messersmith, Todd M Pitts, Anna Capasso, Marileila Varella-Garcia, Peter J Klauck, Jihye Kim, Aik-Choon Tan, S Gail Eckhardt, John J Tentler, John Arcaroli
Patient derived tumor xenograft (PDTX) models provide a necessary platform in facilitating anti-cancer drug development prior to human trials. Human tumor pieces are injected subcutaneously into athymic nude mice (immunocompromised, T cell deficient) to create a bank of tumors and subsequently are passaged into different generations of mice in order to maintain these tumors from patients. Importantly, cellular heterogeneity of the original tumor is closely emulated in this model, which provides a more clinically relevant model for evaluation of drug efficacy studies (single agent and combination), biomarker analysis, resistant pathways and cancer stem cell biology...
September 30, 2016: Journal of Visualized Experiments: JoVE
Christoph Funk, Adrian Roth
Drug-induced liver injury (DILI) is a major concern for drug developers, regulators and clinicians. It is triggered by drug and xenobiotic insults leading to liver impairment or damage, in the worst-case liver failure. In contrast to acute "intrinsic" hepatotoxicity, DILI typically manifests in a very small subset of the population under treatment with no clear dose relationship and inconsistent temporal patterns and is therefore termed an idiosyncratic event. Involved are multifactorial, compound-dependent mechanisms and host-specific factors, making the prediction in preclinical test systems very challenging...
October 20, 2016: Archives of Toxicology
Arathi Kizhedath, Simon Wilkinson, Jarka Glassey
Biopharmaceuticals, monoclonal antibody (mAb)-based therapeutics in particular, have positively impacted millions of lives. MAbs and related therapeutics are highly desirable from a biopharmaceutical perspective as they are highly target specific and well tolerated within the human system. Nevertheless, several mAbs have been discontinued or withdrawn based either on their inability to demonstrate efficacy and/or due to adverse effects. Approved monoclonal antibodies and derived therapeutics have been associated with adverse effects such as immunogenicity, cytokine release syndrome, progressive multifocal leukoencephalopathy, intravascular haemolysis, cardiac arrhythmias, abnormal liver function, gastrointestinal perforation, bronchospasm, intraocular inflammation, urticaria, nephritis, neuropathy, birth defects, fever and cough to name a few...
October 20, 2016: Archives of Toxicology
Beata Powroźnik, Karolina Słoczyńska, Krzysztof Marciniec, Paweł Zajdel, Elżbieta Pękala
Purpose: Determination of the mutagenic potential of new biologically active compounds is of great concern for preliminary toxicity testing and drug development. Methods: The mutagenic and antimutagenic effects of some quinoline- and isoquinolinesulfonamide analogs of aripiprazole (1-8), which display potent antidepressant, anxiolytic, and antipsychotic properties, were evaluated using the Vibrio harveyi assay and OSIRIS Property Explorer software. Additionally, the Ames test was used as the reference. Results: In silico prediction showed that compounds 5 (N-(3-(4-(2,3- dichlorophenyl)piperazin-1-yl)propyl)quinoline-7-sulfonamide) and 6 (N-(4-(4-(2,3- Dichlorophenyl)piperazin-1-yl)butyl)quinoline-7-sulfonamide) trigger a mutagenic structural alert...
September 2016: Advanced Pharmaceutical Bulletin
Shringika Soni, Rakesh Kumar Ruhela, Bikash Medhi
Purpose: For the past few decades central nervous system disorders were considered as a major strike on human health and social system of developing countries. The natural therapeutic methods for CNS disorders limited for many patients. Moreover, nanotechnology-based drug delivery to the brain may an exciting and promising platform to overcome the problem of BBB crossing. In this review, first we focused on the role of the blood-brain barrier in drug delivery; and second, we summarized synthesis methods of nanomedicine and their role in different CNS disorder...
September 2016: Advanced Pharmaceutical Bulletin
Britta Wandschneider, Matthias J Koepp
Functional MRI studies have helped to elucidate underlying mechanisms in complex neurological and neuropsychiatric disorders. Disease processes often involve complex large-scale network interactions, extending beyond the presumed main disease focus. Given both the complexity of the clinical phenotype and the underlying dysfunctional brain circuits, so called pharmaco-fMRI (ph-MRI) studies probe pharmacological effects on functional neuro-anatomy, and can help to determine early treatment response, mechanisms of drug efficacy and side effects, and potentially advance CNS drug development...
2016: NeuroImage: Clinical
David F Tough, Paul P Tak, Alexander Tarakhovsky, Rab K Prinjha
Immune-mediated diseases are clinically heterogeneous but they share genetic and pathogenic mechanisms. These diseases may develop from the interplay of genetic factors and environmental or lifestyle factors. Exposure to such factors, including infectious agents, is associated with coordinated changes in gene transcription owing to epigenetic alterations. A growing understanding of how epigenetic mechanisms control gene expression patterns and cell function has been aided by the development of small-molecule inhibitors that target these processes...
October 21, 2016: Nature Reviews. Drug Discovery
Morten Asser Karsdal, Kim Henriksen, Mette Juul Nielsen, Inger Byrjalsen, Diana Julie Leeming, Stephen Gardner, Zachary Goodman, Keyur Patel, Aleksander Krag, Claus Christiansen, Detlef Schuppan
BACKGROUND: There are no approved treatments for liver fibrosis. To aid development of anti-fibrotic therapies, non-invasive biomarkers that can identify patients with progressive fibrosis and that permit monitoring of the response to anti-fibrotic therapy are much needed. METHODS: Samples from a phase II anti-fibrotic trial of the glitazone farglitazar in patients with advanced hepatitis C, with matched follow-up liver biopsies, and from a phase III study of balaglitazone in late stage type 2 diabetics (BALLET study), were analysed for serological Pro-C3 levels in conjunction with other disease parameters...
October 20, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Naga Chalasani, Arie Regev
No abstract text is available yet for this article.
October 17, 2016: Gastroenterology
M Teresa Donato, Mireia López-Riera, José V Castell, María J Gómez-Lechón, Ramiro Jover
Disruption of the vectorial bile acid transport in the liver is a key feature of cholestatic drugs, although many causal and mechanistic aspects are still unknown. The aim of the present study was to explore if cholestatic drugs can repress or induce the expression of hepatic transporters. To this end, sandwich-cultured rat hepatocytes were treated with cholestatic and non-cholestatic (steatotic, non-hepatotoxic, etc.) drugs and the mRNA expression of 10 uptake and efflux biliary transporters was measured. Results evidenced that all cholestatic drugs cause extensive alterations in the mRNA expression of most biliary transporters...
October 17, 2016: Toxicology Letters
Martín Febles, Sofía Montalvão, Guillermo Díaz Crespín, Manuel Norte, José M Padrón, Päivi Tammela, José J Fernández, Antonio Hernández Daranas
A set of crown ethyl acyl derivatives based on 18-crown-6 moiety was synthesized and evaluated for biological activity. In vitro antiproliferative profiling demonstrated significant activities against HBL-100, HeLa, SW1573 and WiDr human cell lines. The most active compound exhibited GI50 values in the range of 3.7-5.6μM. Antimicrobial evaluation showed that three polyaromatic compounds were active against Staphylococcus aureus (MIC90 values from 8.3μM to 50μM), whereas a (decyloxy)benzene substitution exhibited moderate activity against Candida albicans (MIC90 values 36μM)...
September 29, 2016: Bioorganic & Medicinal Chemistry Letters
Fahima Syeda, Andrew P Holmes, Ting Y Yu, Samantha Tull, Stefan Michael Kuhlmann, Davor Pavlovic, Daniel Betney, Genna Riley, Jan P Kucera, Florian Jousset, Joris R de Groot, Stephan Rohr, Nigel A Brown, Larissa Fabritz, Paulus Kirchhof
BACKGROUND: Antiarrhythmic drugs are widely used to treat patients with atrial fibrillation (AF), but the mechanisms conveying their variable effectiveness are not known. Recent data suggested that paired like homeodomain-2 transcription factor (PITX2) might play an important role in regulating gene expression and electrical function of the adult left atrium (LA). OBJECTIVES: After determining LA PITX2 expression in AF patients requiring rhythm control therapy, the authors assessed the effects of Pitx2c on LA electrophysiology and the effect of antiarrhythmic drugs...
October 25, 2016: Journal of the American College of Cardiology
Büşra Kaya, Belkis Atasever-Arslan, Zeynep Kalkan, Hazal Gür, Bahri Ülküseven
Thiosemicarbozone complexes that have a broad spectrum of biological activity are formed as a result of condensation reaction between thiosemicarbazide [H2N(C=S)-NH-NH2] and carbonyl-containing compounds. A new Nickel(II) complexes with N1-acetylacetone, N4-4-methoxy-salicylidene-thiosemicarbazidato ligand was synthesized and characterized. We studied the antileukemic activity of the Ni(II) thiosemicarbazone compound and assessed their potential for drug development. Specifically, the effects of this Ni(II) thiosemicarbazone compound on intracellular signal nodes and apoptotic pathways were investigated...
October 2016: General Physiology and Biophysics
Nicole Robbins, Gerard D Wright, Leah E Cowen
Invasive fungal infections are becoming an increasingly important cause of human mortality and morbidity, particularly for immunocompromised populations. The fungal pathogens Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus collectively contribute to over 1 million human deaths annually. Hence, the importance of safe and effective antifungal therapeutics for the practice of modern medicine has never been greater. Given that fungi are eukaryotes like their human host, the number of unique molecular targets that can be exploited for drug development remains limited...
October 2016: Microbiology Spectrum
Jian Yang, Jing Yang, Steven H Liang, Yungen Xu, Anna Moore, Chongzhao Ran
In brains of Alzheimer's disease (AD), reactive oxygen species (ROS) levels are significantly higher than that of healthy brains. Evidence suggests that, during AD onset and progression, a vicious cycle revolves around amyloid beta (Aβ) production, aggregation, plaque formation, microglia/immunological responses, inflammation, and ROS production. In this cycle, ROS species play a central role, and H2O2 is one of the most important ROS species. In this report, we have designed a fluorescent imaging probe CRANAD-88, which is capable of cascade amplifying near infrared fluorescence (NIRF) signals at three levels upon interacting with H2O2 in AD brains...
October 20, 2016: Scientific Reports
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