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https://www.readbyqxmd.com/read/28440988/-how-safe-is-the-recombinant-human-growth-hormone
#1
Raúl Calzada-León
In this paper, several aspects related to the safety of the use of biosynthetic human growth hormone are reviewed. For example, its classification as a biosynthetic drug, the phases that need to be performed in Mexico to verify its safety (obtaining, purification, preclinical studies, clinical trials, and finally observational clinical studies), as well as the evidence that exists in relation to the association of intracranial hypertension, muscular events, scoliosis, slipped capital femoral epiphysis, obstructive sleep apnea, pancreatitis, alterations in cortisol, thyroid hormones alterations, cardiovascular disease, metabolic risk, mortality and cancer, adverse events not related to its use, and finally dosing and safety...
May 2017: Revista Médica del Instituto Mexicano del Seguro Social
https://www.readbyqxmd.com/read/28438049/ocular-non-p450-oxidative-reductive-hydrolytic-and-conjugative-drug-metabolizing-enzymes
#2
Upendra A Argikar, Jennifer L Dumouchel, Christine E Dunne, Andrea J Bushee
Metabolism in the eye for any species, laboratory animals or human, is gaining rapid interest as pharmaceutical scientists aim to treat a wide range of so-called incurable ocular diseases. Over a period of decades, reports of metabolic activity toward various drugs and biochemical markers have emerged in select ocular tissues of animals and humans. Ocular P450 enzymes and transporters have been recently reviewed. However, there is a dearth of collated information on non-P450 drug metabolizing enzymes in eyes of various preclinical species and humans in health and disease...
April 24, 2017: Drug Metabolism Reviews
https://www.readbyqxmd.com/read/28432595/what-animal-models-have-taught-us-about-the-safety-and-efficacy-of-bisphosphonates-in-chronic-kidney-disease
#3
REVIEW
Matthew R Allen, Mohammad W Aref
PURPOSE OF REVIEW: Bisphosphonates (BPs) have long been the gold-standard anti-remodeling treatment for numerous metabolic bone diseases. Since these drugs are excreted unmetabolized through the kidney, they are not recommended for individuals with compromised kidney function due to concerns of kidney and bone toxicity. The goal of this paper is to summarize the preclinical BP work in models of kidney disease with particular focus on the bone, kidney, and vasculature. RECENT FINDINGS: Summative data exists showing positive effects on bone and vascular calcifications with minimal evidence for bone or kidney toxicity in animal models...
April 21, 2017: Current Osteoporosis Reports
https://www.readbyqxmd.com/read/28428366/in-vitro-metabolism-of-oprozomib-an-oral-proteasome-inhibitor-role-of-epoxide-hydrolases-and-cytochrome-p450s
#4
Zhican Wang, Ying Fang, Juli Teague, Hansen Wong, Christophe Morisseau, Bruce D Hammock, Dan A Rock, Zhengping Wang
Oprozomib is an oral proteasome inhibitor currently under investigation in patients with hematologic malignancies or solid tumors. Oprozomib elicits potent pharmacological actions by forming a covalent bond with the active site N-terminal threonine of the 20S proteasome. Oprozomib has a short half-life across preclinical species and in patients due to systemic clearance via metabolism. Potential for drug-drug interactions (DDIs) could alter the exposure of this potent therapeutic therefore a thorough investigation of pathways responsible for metabolism is required...
April 20, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28422962/docosahexaenoic-acid-blocks-progression-of-western-diet-induced-nonalcoholic-steatohepatitis-in-obese-ldlr-mice
#5
Kelli A Lytle, Carmen P Wong, Donald B Jump
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in western societies. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is characterized by hepatic steatosis, inflammation, oxidative stress and fibrosis. NASH is a risk factor for cirrhosis and hepatocellular carcinoma. NASH is predicted to be the leading cause of liver transplants by 2020. Despite this growing public health concern, there remain no Food and Drug Administration (FDA) approved NASH treatments...
2017: PloS One
https://www.readbyqxmd.com/read/28408224/one-drug-for-two-targets-biological-evaluation-of-antiretroviral-agents-endowed-with-antiproliferative-activity
#6
Lorenzo Botta, Giorgio Maccari, Pierpaolo Calandro, Marika Tiberi, Annalaura Brai, Claudio Zamperini, Filippo Canducci, Mario Chiariello, Rosa Martí-Centelles, Eva Falomir, Miguel Carda
AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mostly subjects already immunocompromised. The connection between HIV/AIDS and these cancers has not been established yet, but a weakened immune system is certainly the main cause. We envisaged the possibility to screen a small library of compounds synthesized in our laboratory against opportunistic tumors mainly due to HIV infection like Burkitt's Lymphoma. From cellular assays and gene expression analysis we identified two promising compounds...
April 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28399020/therapeutic-micrornas-in-polycystic-kidney-disease
#7
Matanel Yheskel, Vishal Patel
PURPOSE OF REVIEW: microRNAs (miRNAs) are short noncoding RNAs that function as sequence-specific inhibitors of gene expression. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of end-stage kidney failure with limited treatment options. The realization that miRNA upregulation, and thus its gain-of-function, can drive the progression of ADPKD has raised the possibility that anti-miRs represent a novel drug class for this disorder. RECENT FINDINGS: A common set of miRNAs are aberrantly expressed in various murine models of polycystic kidney disease...
April 8, 2017: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/28397099/maturation-of-human-pluripotent-stem-cell-derived-cardiomyocytes-is-improved-in-cardiovascular-construct
#8
Hanna Vuorenpää, Kirsi Penttinen, Tuula Heinonen, Mari Pekkanen-Mattila, Jertta-Riina Sarkanen, Timo Ylikomi, Katriina Aalto-Setälä
In order to translate preclinical data into the clinical studies, relevant in vitro models with structure and key functional properties similar to native human tissue should be used. In vitro cardiac models with vascular structures mimic the highly vascularized myocardium and provide interactions between endothelial cells, stromal cells and cardiomyocytes. Currently, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been shown to present immature morphology and fetal-like electrophysiological properties that may limit their use as physiological test platform...
April 10, 2017: Cytotechnology
https://www.readbyqxmd.com/read/28395380/streptozotocin-treated-high-fat-fed-mice-a-new-type-2-diabetes-model-used-to-study-canagliflozin-induced-alterations-in-lipids-and-lipoproteins
#9
Tian Yu, Mitchell J Sungelo, Ira J Goldberg, Hong Wang, Robert H Eckel
The pharmacological effects of type 2 diabetes (T2DM) medications on lipoprotein metabolism are difficult to assess in preclinical models because those created failure to replicate the human condition in which insulin deficiency is superimposed on obesity-related insulin resistance. To create a better model, we fed mice with high fat (HF) diet and treated the animals with low dose streptozotocin (STZ) to mimic T2DM. We used this model to evaluate the effects of canagliflozin (CANA), a drug that reduces plasma glucose by inhibiting the sodium-glucose transporter 2 (SGLT2), which mediates ~90% of renal glucose reabsorption] on lipid and lipoprotein metabolism...
April 10, 2017: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
https://www.readbyqxmd.com/read/28392555/a-quantitative-analysis-of-statistical-power-identifies-obesity-endpoints-for-improved-in-vivo-preclinical-study-design
#10
J Selimkhanov, W C Thompson, J Guo, K D Hall, C J Musante
The design of well-powered in vivo preclinical studies is a key element in building knowledge of disease physiology for the purpose of identifying and effectively testing potential anti-obesity drug targets. However, as a result of the complexity of the obese phenotype, there is limited understanding of the variability within and between study animals of macroscopic endpoints such as food intake and body composition. This, combined with limitations inherent in the measurement of certain endpoints, presents challenges to study design that can have significant consequences for an anti-obesity program...
April 10, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/28387940/the-bial-10-2474-phase-1-study-a-drug-development-perspective-and-recommendations-for-future-first-in-human-trials
#11
REVIEW
Philip Chaikin
BIA 10-2474 (a fatty acid amide hydrolase inhibitor) was evaluated in a first-in-human phase 1 study in normal volunteers to assess safety/tolerability, pharmacokinetics, pharmacodynamics, and food effect. The dose-escalation process consisted of a single-ascending-dose phase (SAD) and multiple-ascending-dose phase (MAD). Prospective determination of the starting dose and maximal escalated dose was consistent with the usual clinical pharmacology principles for extrapolation of preclinical toxicology data to human equivalent doses...
April 7, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28382857/prediction-of-human-intestinal-absorption-of-compounds-using-artificial-intelligence-techniques
#12
Rajnish Kumar, Anju Sharma, Mohammed Haris Siddiqui, Rajesh Kumar Tiwari
Information about Pharmacokinetics of compounds is an essential component of drug design and development. Modeling the pharmacokinetic properties require identification of the factors effecting absorption, distribution, metabolism and excretion of compounds. There have been continuous attempts in the prediction of absorption of compounds using various Artificial intelligence methods in the effort to reduce the attrition rate of drug candidates entering to preclinical and clinical trials. Currently, there are large numbers of individual predictive models available for absorption using machine learning approaches...
April 4, 2017: Current Drug Discovery Technologies
https://www.readbyqxmd.com/read/28382685/dimethyl-fumarate-ameliorates-myoclonus-stemming-from-protein-misfolding-in-oligodendrocytes
#13
Cherie M Southwood, Danielle M Garshott, Chelsea R Richardson, Navid Seraji-Bozorgzad, Andrew M Fribley, Alexander Gow
Multiple sclerosis (MS) is considered a primary autoimmune disease; however, this view is increasingly being challenged in basic and clinical science arenas because of the growing body of clinical trials data showing that exclusion of immune cells from the CNS only modestly slows disease progression to disability. Accordingly, there is significant need for expanding the scope of potential disease mechanisms to understand the etiology of MS. Concomitantly, the use of a broader range of preclinical animal models for characterizing existing efficacious clinical treatments may elucidate additional or unexpected mechanisms of action for these drugs that augment insight into MS etiology...
April 6, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28351863/systems-chronotherapeutics
#14
REVIEW
Annabelle Ballesta, Pasquale F Innominato, Robert Dallmann, David A Rand, Francis A Lévi
Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system...
April 2017: Pharmacological Reviews
https://www.readbyqxmd.com/read/28351381/the-role-of-stromal-cancer-associated-fibroblasts-in-pancreatic-cancer
#15
REVIEW
Dagny von Ahrens, Tushar D Bhagat, Deepak Nagrath, Anirban Maitra, Amit Verma
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer generally refractory to conventional treatments. Cancer-associated fibroblasts (CAFs) are cellular components of the desmoplastic stroma characteristic to the tumor that contributes to this treatment resistance. Various markers for CAFs have been explored including palladin and CD146 that have prognostic and functional roles in the pathobiology of PDAC. Mechanisms of CAF-tumor cell interaction have been described including exosomal transfer and paracrine signaling mediated by cytokines such as GM-CSF and IL-6...
March 28, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28344661/liposomal-irinotecan-in-gemcitabine-refractory-metastatic-pancreatic-cancer-efficacy-safety-and-place-in-therapy
#16
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
#17
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
#18
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
#19
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
#20
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
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