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https://www.readbyqxmd.com/read/29351570/joint-adolescent-adult-early-phase-clinical-trials-to-improve-access-to-new-drugs-for-adolescents-with-cancer-proposals-from-the-multi-stakeholder-platform-accelerate
#1
N Gaspar, L V Marshall, D Binner, R Herold, R Rousseau, P Blanc, R Capdeville, J Carleer, C Copland, Y Kerloeguen, K Norga, L Pacaud, M-A Sevaux, C Spadoni, J Sterba, F Ligas, T Taube, M Uttenreuther-Fischer, S Chioato, M A O'Connell, B Geoerger, J-Y Blay, J C Soria, S Kaye, B Wulff, L Brugières, G Vassal, A D J Pearson
The impressive progress recently observed in adult cancers through the introduction of new drugs has not yet been translated to adolescents between 12 and 17 years of age. Currently adolescents are grouped with children, so their access to new, effective drugs already available for adults is delayed because paediatric drug development starts late relative to adult programmes. Moreover, specific early phase trials designed exclusively for adolescents in rare diseases recruit poorly, even if conducted internationally...
January 16, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29348854/acid-ceramidase-and-its-inhibitors-a-de-novo-drug-target-and-a-new-class-of-drugs-for-killing-glioblastoma-cancer-stem-cells-with-high-efficiency
#2
Ninh B Doan, Hisham Alhajala, Mona M Al-Gizawiy, Wade M Mueller, Scott D Rand, Jennifer M Connelly, Elizabeth J Cochran, Christopher R Chitambar, Paul Clark, John Kuo, Kathleen M Schmainda, Shama P Mirza
Glioblastoma remains the most common, malignant primary cancer of the central nervous system with a low life expectancy and an overall survival of less than 1.5 years. The treatment options are limited and there is no cure. Moreover, almost all patients develop recurrent tumors, which typically are more aggressive. Therapeutically resistant glioblastoma or glioblastoma stem-like cells (GSCs) are hypothesized to cause this inevitable recurrence. Identifying prognostic biomarkers of glioblastoma will potentially advance knowledge about glioblastoma tumorigenesis and enable discovery of more effective therapies...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348681/impact-of-a-five-dimensional-framework-on-r-d-productivity-at-astrazeneca
#3
REVIEW
Paul Morgan, Dean G Brown, Simon Lennard, Mark J Anderton, J Carl Barrett, Ulf Eriksson, Mark Fidock, Bengt Hamrén, Anthony Johnson, Ruth E March, James Matcham, Jerome Mettetal, David J Nicholls, Stefan Platz, Steve Rees, Michael A Snowden, Menelas N Pangalos
In 2011, AstraZeneca embarked on a major revision of its research and development (R&D) strategy with the aim of improving R&D productivity, which was below industry averages in 2005-2010. A cornerstone of the revised strategy was to focus decision-making on five technical determinants (the right target, right tissue, right safety, right patient and right commercial potential). In this article, we describe the progress made using this '5R framework' in the hope that our experience could be useful to other companies tackling R&D productivity issues...
January 19, 2018: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29348557/sensitizing-tumor-cells-to-conventional-drugs-hsp70-chaperone-inhibitors-their-selection-and-application-in-cancer-models
#4
Vladimir F Lazarev, Dmitry V Sverchinsky, Elena R Mikhaylova, Pavel I Semenyuk, Elena Y Komarova, Sergey A Niskanen, Alina D Nikotina, Anton V Burakov, Viktor G Kartsev, Irina V Guzhova, Boris A Margulis
Hsp70 chaperone controls proteostasis and anti-stress responses in rapidly renewing cancer cells, making it an important target for therapeutic compounds. To date several Hsp70 inhibitors are presented with remarkable anticancer activity, however their clinical application is limited by the high toxicity towards normal cells. This study aimed to develop assays to search for the substances that reduce the chaperone activity of Hsp70 and diminish its protective function in cancer cells. On our mind the resulting compounds alone should be safe and function in combination with drugs widely employed in oncology...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29348271/intratumoral-payload-concentration-correlates-with-the-activity-of-antibody-drug-conjugates
#5
Donglu Zhang, Shang-Fan Yu, S Cyrus Khojasteh, Yong Ma, Thomas H Pillow, Jack D Sadowsky, Dian Su, Katherine R Kozak, Keyang Xu, Andrew G Polson, Peter Dragovich, Cornelis Eca Hop
Antibody-drug conjugates (ADCs) have become important scaffolds for targeted cancer therapies. However, ADC exposure - response correlation is not well characterized. We demonstrated that intratumor payload exposures correlated well with the corresponding efficacies of several disulfide-linked ADCs bearing an DNA alkylating agent, pyrrolo[2,1-c][1,4]benzodiazepine-dimer (PBD), in HER2-expressing xenograft models. The correlation suggests that a threshold concentration of intratumor payload is required to support sustained efficacy and an ADC can deliver an excessive level of payload to tumors that does not enhance efficacy ('Plateau' effect)...
January 18, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29348125/metabolism-and-disposition-of-a-novel-selective-%C3%AE-7-neuronal-acetylcholine-receptor-agonist-abt-126-in-humans-characterization-of-the-major-roles-for-flavin-containing-monooxygenases-and-udp-glucuronosyl-transferase-1a4-and-2b10-in-catalysis
#6
Hong Liu, David M Stresser, Melissa J Michmerhuizen, XIaofeng Li, Ahmed A Othman, Aimee D Reed, Michael R Schrimpf, Jens Sydor, Anthony J Lee
Mass balance, metabolism and excretion of ABT-126, an α7 nAChRs agonist, were characterized in healthy male subjects (n=4) following a single 100 mg (100 μCi) oral dose. The total recovery of the administered radioactivity was 94.0% (±2.09%) with 81.5% (± 10.2%) in urine and 12.4% (± 9.3%) in feces. Metabolite profiling indicated that ABT-126 had been extensively metabolized with 6.6% of the dose remaining as unchanged parent drug in urine. Parent drug accounted for 12.2% of the administered radioactivity in feces...
January 18, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29346478/differentiation-syndrome-associated-with-enasidenib-a-selective-inhibitor-of-mutant-isocitrate-dehydrogenase-2-analysis-of-a-phase-1-2-study
#7
Amir T Fathi, Courtney D DiNardo, Irina Kline, Laurie Kenvin, Ira Gupta, Eyal C Attar, Eytan M Stein, Stephane de Botton
Importance: Enasidenib mesylate, a mutant isocitrate dehydrogenase 2 (IDH2) protein inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by the US Food and Drug Administration for use in relapsed/refractory (R/R) mutant IDH2 acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity...
January 18, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29343694/sertraline-paroxetine-and-chlorpromazine-are-rapidly-acting-anthelmintic-drugs-capable-of-clinical-repurposing
#8
Janis C Weeks, William M Roberts, Caitlyn Leasure, Brian M Suzuki, Kristin J Robinson, Heather Currey, Phurpa Wangchuk, Ramon M Eichenberger, Aleen D Saxton, Thomas D Bird, Brian C Kraemer, Alex Loukas, John M Hawdon, Conor R Caffrey, Nicole F Liachko
Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs. To expedite drug discovery, we screened a small-molecule library of compounds with histories of use in human clinical trials for anthelmintic activity against the soil nematode Caenorhabditis elegans. From this screen, we found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae and gravid adults...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29343567/parainfluenza-virus-infection-sensitizes-cancer-cells-to-dna-damaging-agents-implications-for-oncolytic-virus-therapy
#9
Candace R Fox, Griffith D Parks
We have previously shown that the Parainfluenza virus 5 (PIV5) mutant P/V-CPI- is restricted for spread in normal cells but not in cancer cells in vitro and is effective at reducing tumor burden in mouse model systems. Here we show that P/V-CPI- infection of human laryngeal cancer HEp-2 cells results in the majority of the cells dying, but unexpectedly, over time there is an emergence of a population of cells which survive as P/V-CPI- persistently infected (PI) cells. P/V-CPI- PI cells had elevated levels of basal caspase activation, and viability was highly dependent on activity of cellular inhibitors of apoptosis (IAPs) such as Survivin and XIAP...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29343553/molecular-mechanisms-of-biased-and-probe-dependent-signaling-at-cxcr3-induced-by-negative-allosteric-modulators
#10
Regine Brox, Lampros Milanos, Noureldin Saleh, Paul Baumeister, Armin Buschauer, Dagmar Hofmann, Markus R Heinrich, Timothy Clark, Nuska Tschammer
Our recent explorations of allosteric modulators (AMs) with improved properties resulted in the identification of two biased negative AMs, N-1-{[3-(4-Ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimi-din2yl]ethyl}-4-(4-fluorobutoxy)-N-[(1-methylpiperidin-4-yl)me-thyl}]butanamide (BD103) and {5-[(N-{1-[3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl-2-[4-fluoro-3-(trifluoromethyl)phenyl]acetamido)methyl]-2-fluorophenyl}boronic acid (BD064), that exhibited probe-dependent inhibition of the chemokine receptor CXCR3 signaling...
January 17, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29343444/activation-of-p53-in-immature-myeloid-precursor-cells-controls-differentiation-into-ly6c-cd103-monocytic-antigen-presenting-cells-in-tumors
#11
Madhav D Sharma, Paulo C Rodriguez, Brent H Koehn, Babak Baban, Yan Cui, Gang Guo, Michiko Shimoda, Rafal Pacholczyk, Huidong Shi, Eun-Joon Lee, Hongyan Xu, Theodore S Johnson, Yukai He, Taha Mergoub, Christopher Venable, Vincenzo Bronte, Jedd D Wolchok, Bruce R Blazar, David H Munn
CD103+ dendritic cells are critical for cross-presentation of tumor antigens. Here we have shown that during immunotherapy, large numbers of cells expressing CD103 arose in murine tumors via direct differentiation of Ly6c+ monocytic precursors. These Ly6c+CD103+ cells could derive from bone-marrow monocytic progenitors (cMoPs) or from peripheral cells present within the myeloid-derived suppressor cell (MDSC) population. Differentiation was controlled by inflammation-induced activation of the transcription factor p53, which drove upregulation of Batf3 and acquisition of the Ly6c+CD103+ phenotype...
January 16, 2018: Immunity
https://www.readbyqxmd.com/read/29343259/influence-of-apocynin-on-cardiac-remodeling-in-rats-with-streptozotocin-induced-diabetes-mellitus
#12
R Gimenes, C Gimenes, C M Rosa, N P Xavier, D H S Campos, A A H Fernandes, M D M Cezar, G N Guirado, L U Pagan, I D Chaer, D C Fernandes, F R Laurindo, A C Cicogna, M P Okoshi, K Okoshi
BACKGROUND: Increased reactive oxygen species (ROS) generation in diabetes mellitus (DM) is an important mechanism leading to diabetic cardiomyopathy. Apocynin, a drug isolated from the herb Picrorhiza kurroa, is considered an antioxidant agent by inhibiting NADPH oxidase activity and improving ROS scavenging. This study analyzed the influence of apocynin on cardiac remodeling in diabetic rats. METHODS: Six-month-old male Wistar rats were assigned into 4 groups: control (CTL, n = 15), control + apocynin (CTL + APO, n = 20), diabetes (DM, n = 20), and diabetes + apocynin (DM + APO, n = 20)...
January 17, 2018: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/29343012/-the-effectiveness-of-individualized-treatment-regimen-on-smear-positive-retreatment-pulmonary-tuberculosis-with-mono-and-poly-drug-resistance
#13
Y H Liu, W W Gao, L Li, J Du, Y Ma, W Shu, X Y Lyu, S H Xie, H H Wang, T Chen
Objective: To analyze and evaluate the effectiveness of individualized treatment regimen in the therapy of smear-positive retreatment pulmonary tuberculosis with mono-and poly-drug resistance, and therefor to provide information on how to develop rational individualized regimen for retreatment tuberculosis cases with drug resistance. Methods: This was a multi-centered, prospective cohort study. Totally 254 cases of sputum positive tuberculosis with previous treatment history during the period from July 1, 2009 to August 30, 2016 were included in the analysis...
January 12, 2018: Chinese Journal of Tuberculosis and Respiratory Diseases
https://www.readbyqxmd.com/read/29341164/patient-derived-organoid-models-help-define-personalized-management-of-gastrointestinal-cancer
#14
REVIEW
M R Aberle, R A Burkhart, H Tiriac, S W M Olde Damink, C H C Dejong, D A Tuveson, R M van Dam
BACKGROUND: The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient-derived three-dimensional 'organoid' models...
January 2018: British Journal of Surgery
https://www.readbyqxmd.com/read/29340530/the-use-of-biosimilar-medicines-in-oncology-position-statement-of-the-brazilian-society-of-clinical-oncology-sboc
#15
G S Fernandes, C Sternberg, G Lopes, R Chammas, M A C Gifoni, R A Gil, D V Araujo
A biosimilar is a biologic product that is similar to a reference biopharmaceutical product, the manufacturing process of which hinders the ability to identically replicate the structure of the original product, and therefore, it cannot be described as an absolute equivalent of the original medication. The currently available technology does not allow for an accurate copy of complex molecules, but it does allow the replication of similar molecules with the same activity. As biosimilars are about to be introduced in oncology practice, these must be evaluated through evidence-based medicine...
January 11, 2018: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/29339392/a-novel-piperazine-based-drug-lead-for-cryptosporidiosis-from-the-medicines-for-malaria-venture-open-access-malaria-box
#16
R S Jumani, K Bessoff, M S Love, P Miller, E E Stebbins, J E Teixeira, M A Campbell, M J Meyers, J A Zambriski, V Nunez, A K Woods, C W McNamara, C D Huston
Cryptosporidiosis causes life-threatening diarrhea in children under age five, and prolonged diarrhea in immunodeficient people, especially AIDS patients. The standard of care, nitazoxanide, is modestly effective in children and ineffective in immunocompromised individuals. In addition to a need for new drugs, better knowledge of drug properties that drive in vivo efficacy is needed to facilitate drug development. We report identification of a piperazine-based lead compound for Cryptosporidium drug development, MMV665917, and a new pharmacodynamic method used for its characterization...
January 16, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29339288/hyaluronic-acid-in-pluronic-f-127-f-108-hydrogels-for-postoperative-pain-in-arthroplasties-influence-on-physico-chemical-properties-and-structural-requirements-for-sustained-drug-release
#17
M H M Nascimento, M K K D Franco, F Yokaichyia, E de Paula, C B Lombello, D R de Araujo
In this study, we reported the hyaluronic acid (HA) on supramolecular structure of Pluronic F-127 (PLF-127) and/or Pluronic F-108 (PLF-127) hydrogels, as well as their effects on release mechanisms, looking forward their application as lidocaine (LDC) drug-delivery systems in arthroplastic surgeries. We have studied the HA-micelle interaction using Dynamic Light Scattering (DLS), the micellization and sol-gel transition processes by Differential Scanning Calorimetry (DSC) and Rheology., of PL-based hydrogels and...
January 12, 2018: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29338962/knowledge-on-asthma-food-allergies-and-anaphylaxis-assessment-of-elementary-school-teachers-parents-caregivers-of-asthmatic-children-and-university-students-in-uruguaiana-in-the-state-of-rio-grande-do-sul-brazil
#18
M Urrutia-Pereira, L P Mocellin, R B de Oliveira, L Simon, L Lessa, D Solé
INTRODUCTION: Allergic diseases have become an increasingly common reality in the last years, extending beyond the family context. OBJECTIVE: Assessing the level of knowledge on asthma, food allergies and anaphylaxis of asthmatic children's parents/caregivers (PC), elementary school teachers (EST) and university students (US) in Uruguaiana, RS, Brazil. METHOD: 577 individuals (PC - N=111; EST - N=177; US - N=299) took part in the study, answering the Newcastle Asthma Knowledge Questionnaire (validated for Portuguese) and another questionnaire on Food Allergy (FA) and anaphylaxis...
January 12, 2018: Allergologia et Immunopathologia
https://www.readbyqxmd.com/read/29338735/mental-health-service-utilization-is-associated-with-retention-in-care-among-persons-living-with-hiv-at-a-university-affiliated-hiv-clinic
#19
Lauren A Saag, Ashutosh R Tamhane, D Scott Batey, Michael J Mugavero, Ellen F Eaton
BACKGROUND: Mental health (MH) comorbidities reduce retention in care for persons living with HIV (PLWH) and are associated with poor health outcomes. Optimizing retention in primary care is vital, as poor retention is associated with delayed receipt of antiretroviral (ARV) therapy, ARV non-adherence, and poor health outcomes, including failure to suppress viral load, decreased CD4 counts, and clinically significant ARV drug resistance. We hypothesized that MH service utilization would be associated with improved retention in care for patients with HIV and MH comorbidities...
January 16, 2018: AIDS Research and Therapy
https://www.readbyqxmd.com/read/29338612/gene-profiling-of-nucleus-basalis-tau-containing-neurons-in-chronic-traumatic-encephalopathy-a-chronic-effects-of-neurotrauma-consortium-study
#20
Elliott Jay Mufson, Bin He, Stephen D Ginsberg, Benjamin A Carper, Gayle S Bieler, Fiona C Crawford, Victor E Alverez, Bernard R Huber, Thor D Stein, Ann C McKee, Sylvia E Perez
Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increasing number of NFTs across the pathological stages of CTE...
January 16, 2018: Journal of Neurotrauma
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