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https://www.readbyqxmd.com/read/28344661/liposomal-irinotecan-in-gemcitabine-refractory-metastatic-pancreatic-cancer-efficacy-safety-and-place-in-therapy
#1
REVIEW
Emma Kipps, Kate Young, Naureen Starling
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy...
March 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28341160/metabolic-network-failures-in-alzheimer-s-disease-a-biochemical-road%C3%A2-map
#2
Jon B Toledo, Matthias Arnold, Gabi Kastenmüller, Rui Chang, Rebecca A Baillie, Xianlin Han, Madhav Thambisetty, Jessica D Tenenbaum, Karsten Suhre, J Will Thompson, Lisa St John-Williams, Siamak MahmoudianDehkordi, Daniel M Rotroff, John R Jack, Alison Motsinger-Reif, Shannon L Risacher, Colette Blach, Joseph E Lucas, Tyler Massaro, Gregory Louie, Hongjie Zhu, Guido Dallmann, Kristaps Klavins, Therese Koal, Sungeun Kim, Kwangsik Nho, Li Shen, Ramon Casanova, Sudhir Varma, Cristina Legido-Quigley, M Arthur Moseley, Kuixi Zhu, Marc Y R Henrion, Sven J van der Lee, Amy C Harms, Ayse Demirkan, Thomas Hankemeier, Cornelia M van Duijn, John Q Trojanowski, Leslie M Shaw, Andrew J Saykin, Michael W Weiner, P Murali Doraiswamy, Rima Kaddurah-Daouk
INTRODUCTION: The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance...
March 21, 2017: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/28335648/inflammation-and-pharmacokinetics-potential-implications-for-hiv-infection
#3
Sharon M Seifert, Jose R Castillo-Mancilla, Kristine M Erlandson, Peter L Anderson
The physiological changes accompanying inflammation may alter the pharmacokinetics (PK) of certain medications. Individuals infected with HIV have chronically elevated inflammatory markers despite viral suppression following effective antiretroviral therapy (ART), as well as age-related inflammation. Understanding the potential clinical implications of inflammation on the PK of medications is important for understanding dose-response relationships and necessitates future research. Areas covered: An extensive literature search was carried out using PubMed and associated bibliographies to summarize the current state of knowledge regarding altered PK in response to inflammation and its application to the field of HIV...
March 24, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28327633/cardiac-drug-drug-interaction-between-hcv-ns5b-pronucleotide-inhibitors-and-amiodarone-is-determined-by-their-specific-diastereochemistry
#4
Armando Lagrutta, Christopher P Regan, Haoyu Zeng, John P Imredy, Kenneth Koeplinger, Pierre Morissette, Liping Liu, Gordon Wollenberg, Christopher Brynczka, José Lebrón, Joseph DeGeorge, Frederick Sannajust
Severe bradycardia/bradyarrhythmia following coadministration of the HCV-NS5B prodrug sofosbuvir with amiodarone was recently reported. Our previous preclinical in vivo experiments demonstrated that only certain HCV-NS5B prodrugs elicit bradycardia when combined with amiodarone. In this study, we evaluate the impact of HCV-NS5B prodrug phosphoramidate diastereochemistry (D-/L-alanine, R-/S-phosphoryl) in vitro and in vivo. Co-applied with amiodarone, L-ala,SP prodrugs increased beating rate and decreased beat amplitude in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), but D-ala,RP produgs, including MK-3682, did not...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28324269/metformin-sensitizes-triple-negative-breast-cancer-to-proapoptotic-trail-receptor-agonists-by-suppressing-xiap-expression
#5
Elena Strekalova, Dmitry Malin, Harisha Rajanala, Vincent L Cryns
PURPOSE: Despite robust antitumor activity in diverse preclinical models, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have not demonstrated efficacy in clinical trials, underscoring the need to identify agents that enhance their activity. We postulated that the metabolic stress induced by the diabetes drug metformin would sensitize breast cancer cells to TRAIL receptor agonists. METHODS: Human triple (estrogen receptor, progesterone receptor, and HER2)-negative breast cancer (TNBC) cell lines were treated with TRAIL receptor agonists (monoclonal antibodies or TRAIL peptide), metformin, or the combination...
March 21, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28322141/lessons-learned-from-gemcitabine-impact-of-therapeutic-carrier-systems-and-gemcitabine-s-drug-conjugates-on-cancer-therapy
#6
REVIEW
Sathish Dyawanapelly, Animesh Kumar, Manish K Chourasia
Currently, drug delivery systems have a high impact in cancer therapy and are receiving more attention than conventional cancer treatment modalities. Compared with current cancer therapies, gemcitabine (2', 2'-difluoro-2'-deoxycytidine) has been proven to be an effective chemotherapeutic agent against pancreatic, colon, bladder, breast, ovarian, non-small-cell lung, and head and neck cancers in combination with other anticancer agents. To improve the safety and efficacy of cytotoxic drugs, several drug delivery systems have been explored...
2017: Critical Reviews in Therapeutic Drug Carrier Systems
https://www.readbyqxmd.com/read/28304309/mouse-models-of-alzheimer-s-disease
#7
Gisela Esquerda-Canals, Laia Montoliu-Gaya, Jofre Güell-Bosch, Sandra Villegas
Alzheimer's disease (AD) is a neurodegenerative disorder that nowadays affects more than 40 million people worldwide and it is predicted to exponentially increase in the coming decades. Because no curative treatment exists, research on the pathophysiology of the disease, as well as the testing of new drugs, are mandatory. For these purposes, animal models constitute a valuable, although perfectible tool. This review takes a tour through several aspects of mouse models of AD, such as the generation of transgenic models, the relevance of the promoter driving the expression of the transgenes, and the concrete transgenes used to simulate AD pathophysiology...
March 10, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28302026/drug-metabolism-in-preclinical-drug-development-a-survey-of-the-discovery-process-toxicology-and-computational-tools
#8
Naiem T Issa, Henri Wathieu, Abiola Ojo, Stephen W Byers, Sivanesan Dakshanamurthy
Increased R & D spending and high failure rates exist in drug development, due in part to inadequate prediction of drug metabolism and its consequences in the human body. Hence, there is a need for computational methods to supplement and complement current biological assessment strategies. In this review, we provide an overview of drug metabolism in pharmacology, and discuss the current in vitro and in vivo strategies for assessing drug metabolism in preclinical drug development. We highlight computational tools available to the scientific community for the in silico prediction of drug metabolism, and examine how these tools have been implemented to produce drug-target signatures relevant to metabolic routes...
March 15, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/28301873/personalising-and-targeting-antiangiogenic-resistance-a-complex-and-multifactorial-approach
#9
REVIEW
Maria J Bueno, Silvana Mouron, Miguel Quintela-Fandino
Pathological angiogenesis involves complex and dynamic interactions between tumour cells and other lineages existing in the microenvironment of the tumour. Preclinical and clinical data suggest that tumours can show dual, different adaptive responses against antiangiogenic agents: one successful adaptation is vascular normalisation, whereas the second adaptation is elicited through vascular trimming and increased hypoxia. These phenomena depend on the type of tumour and the type of agent. The classical approach for investigating acquired resistance against antiangiogenic agents is to identify compensatory signalling pathways emerging in response to VEGF blockade, which has led to the development of highly effective drugs; however, ultimately these drugs fail...
March 16, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28298268/effects-of-dietary-flavonoids-on-reverse-cholesterol-transport-hdl-metabolism-and-hdl-function
#10
REVIEW
Courtney L Millar, Quinn Duclos, Christopher N Blesso
Strong experimental evidence confirms that HDL directly alleviates atherosclerosis. HDL particles display diverse atheroprotective functions in reverse cholesterol transport (RCT), antioxidant, anti-inflammatory, and antiapoptotic processes. In certain inflammatory disease states, however, HDL particles may become dysfunctional and proatherogenic. Flavonoids show the potential to improve HDL function through their well-documented effects on cellular antioxidant status and inflammation. The aim of this review is to summarize the basic science and clinical research examining the effects of dietary flavonoids on RCT and HDL function...
March 2017: Advances in Nutrition
https://www.readbyqxmd.com/read/28297582/human-stem-cell-derived-endothelial-hepatic-platform-for-efficacy-testing-of-vascular-protective-metabolites-from-nutraceuticals
#11
Balakrishnan Chakrapani Narmada, Yeek Teck Goh, Huan Li, Sanjay Sinha, Hanry Yu, Christine Cheung
Atherosclerosis underlies many cardiovascular and cerebrovascular diseases. Nutraceuticals are emerging as a therapeutic moiety for restoring vascular health. Unlike small-molecule drugs, the complexity of ingredients in nutraceuticals often confounds evaluation of their efficacy in preclinical evaluation. It is recognized that the liver is a vital organ in processing complex compounds into bioactive metabolites. In this work, we developed a coculture system of human pluripotent stem cell-derived endothelial cells (hPSC-ECs) and human pluripotent stem cell-derived hepatocytes (hPSC-HEPs) for predicting vascular-protective effects of nutraceuticals...
March 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/28284817/differential-effects-of-gaseous-versus-injectable-anesthetics-on-changes-in-regional-cerebral-blood-flow-and-metabolism-induced-by-l-dopa-in-a-rat-model-of-parkinson-s-disease
#12
Zisis Bimpisidis, Carl M Öberg, Natallia Maslava, M Angela Cenci, Cornelia Lundblad
Preclinical imaging of brain activity requires the use of anesthesia. In this study, we have compared the effects of two widely used anesthetics, inhaled isoflurane and ketamine/xylazine cocktail, on cerebral blood flow and metabolism in a rat model of Parkinson's disease and l-DOPA-induced dyskinesia. Specific tracers were used to estimate regional cerebral blood flow (rCBF - [(14)C]-iodoantipyrine) and regional cerebral metabolic rate (rCMR - [(14)C]-2-deoxyglucose) with a highly sensitive autoradiographic method...
March 8, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28283392/addictions-neuroclinical-assessment-a-reverse-translational-approach
#13
REVIEW
Laura E Kwako, Reza Momenan, Erica N Grodin, Raye Z Litten, David Goldman
Incentive salience, negative emotionality, and executive function are functional domains that are etiologic in the initiation and progression of addictive disorders, having been implicated in humans with addictive disorders and in animal models of addictions. Measures of these three neuroscience-based functional domains can capture much of the effects of inheritance and early exposures that lead to trait vulnerability shared across different addictive disorders. For specific addictive disorders, these measures can be supplemented by agent specific measures such as those that access pharmacodynamic and pharmacokinetic variation attributable to agent-specific gatekeeper molecules including receptors and drug-metabolizing enzymes...
March 7, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28271897/branched-chain-amino-acids-as-predictors-for-individual-differences-of-cisplatin-nephrotoxicity-in-rats-a-pharmacometabonomics-study
#14
Pei Zhang, Wei Li, Jiaqing Chen, Ruiting Li, Zunjian Zhang, Yin Huang, Fengguo Xu
Nephrotoxicity is the dose-limiting adverse effect of cisplatin with large individual differences. Up to now, little has been done on how to recognize and predict the individual differences in either preclinical or clinical research. In the present study, important postdose indicators were screened out first and integrated into a grouping factor, according to which rats were recognized as lowly or highly sensitive individuals. Then, mass-spectrometry-based untargeted metabolomics approach was performed to dissect the metabolic differences in predose serum of the two groups...
March 17, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28263602/aldehyde-oxidase-mediated-metabolism-in-drug-like-molecules-a-combined-computational-and-experimental-study
#15
Yuan Xu, Liang Li, Yulan Wang, Jing Xing, Lei Zhou, Dafang Zhong, Xiaomin Luo, Hualiang Jiang, Kaixian Chen, Mingyue Zheng, Pan Deng, Xiaoyan Chen
Aldehyde oxidase (AOX) is an important drug-metabolizing enzyme. However, the current in vitro models for evaluating AOX metabolism are sometimes misleading, and preclinical animal models generally fail to predict human AOX-mediated metabolism. In this study, we report a combined computational and experimental investigation of drug-like molecules that are potential aldehyde oxidase substrates, of which multiple sites of metabolism (SOMs) mediated by AOX and their preferences for the reaction can be unambiguously identified...
March 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28261547/progress-in-prediction-and-interpretation-of-clinically-relevant-metabolic-drug-drug-interactions-a-minireview-illustrating-recent-developments-and-current-opportunities
#16
REVIEW
Stephen Fowler, Peter N Morcos, Yumi Cleary, Meret Martin-Facklam, Neil Parrott, Michael Gertz, Li Yu
PURPOSE OF REVIEW: This review gives a perspective on the current "state of the art" in metabolic drug-drug interaction (DDI) prediction. We highlight areas of successful prediction and illustrate progress in areas where limits in scientific knowledge or technologies prevent us from having full confidence. RECENT FINDINGS: Several examples of success are highlighted. Work done for bitopertin shows how in vitro and clinical data can be integrated to give a model-based understanding of pharmacokinetics and drug interactions...
2017: Current Pharmacology Reports
https://www.readbyqxmd.com/read/28258674/ibudilast-a-non%C3%A2-selective-phosphodiesterase-inhibitor-in-brain-disorders
#17
Joanna Schwenkgrub, Małgorzata Zaremba, Dagmara Mirowska-Guzel, Iwona Kurkowska-Jastrzębska
Ibudilast (IBD) is a non‑selective (3, 4, 10, 11) phosphodiesterase (PDE) inhibitor, used mainly as a bronchodilator for the treatment of bronchial asthma. PDE play a central role in cellular function (e.g. differentiation, synaptic plasticity and inflammatory response) by metabolizing cyclic nucleotides. The results from preclinical and clinical studies indicate that IBD has a broader range of action through suppression of pro‑inflammatory cytokines (IL‑6, IL‑1β, TNF‑α), toll‑like receptor 4 blockade (TLR‑4), inhibition of a macrophage migration inhibitory factor (MIF), up‑regulation the anti‑inflammatory cytokine (IL‑10), and promotion of neurotrophic factors (GDNF, NGF, NT‑4)...
March 2, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/28258069/marmoset-flavin-containing-monooxygenase-3-in-liver-is-a-major-benzydamine-and-sulindac-sulfide-oxygenase
#18
Shotaro Uehara, Makiko Shimizu, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus) are potentially primate models for preclinical drug metabolism studies because the molecular characteristics of cytochrome P450 (P450) enzymes have similarities between this species and humans. However, characterization of non-P450 enzymes have not been clarified in marmosets. Here, we report characterization of flavin-containing monooxygenase (FMO) 1-5 identified in marmoset tissues. Marmoset FMO forms shared high amino acid sequence identities (93-95%) and phylogenetic closeness with human homologue FMO forms...
March 3, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28251104/effect-of-dipeptidyl-peptidase-4-inhibitors-on-acute-and-subacute-models-of-inflammation-in-male-wistar-rats-an-experimental-study
#19
Urmila Anil Kagal, Netravathi Basavaraj Angadi, Somnath Mallikarjun Matule
INTRODUCTION: The prevalence of Type 2 diabetes mellitus (T2DM) has reached alarming proportions due to the rapidly increasing rates of this disease worldwide. Preclinical and clinical studies have revealed elevated levels of inflammatory markers in a vast number of illnesses such as T2DM, obesity, and atherothrombosis collectively called metabolic syndrome leading to adverse cardiovascular events. Dipeptidyl peptidase 4 (DPP-4) inhibitors which are the enhancers of glucagon-like peptide 1 (GLP -1), could have anti-inflammatory potential which could help in reducing cardiovascular complications of diabetes and benefit patients suffering from the metabolic syndrome...
January 2017: International Journal of Applied and Basic Medical Research
https://www.readbyqxmd.com/read/28244639/selective-elimination-of-neuroblastoma-cells-by-synergistic-effect-of-akt-kinase-inhibitor-and-tetrathiomolybdate
#20
Jarmila Navrátilová, Martina Karasová, Martina Kohutková Lánová, Ludmila Jiráková, Zuzana Budková, Jiří Pacherník, Jan Šmarda, Petr Beneš
Neuroblastoma is the most common extracranial solid tumour of infancy. Pathological activation of glucose consumption, glycolysis and glycolysis-activating Akt kinase occur frequently in neuroblastoma cells, and these changes correlate with poor prognosis of patients. Therefore, several inhibitors of glucose utilization and the Akt kinase activity are in preclinical trials as potential anti-cancer drugs. However, metabolic plasticity of cancer cells might undermine efficacy of this approach. In this work, we identified oxidative phosphorylation as compensatory mechanism preserving viability of neuroblastoma cells with inhibited glucose uptake/Akt kinase...
February 28, 2017: Journal of Cellular and Molecular Medicine
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