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drug metabolism, preclinical

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https://www.readbyqxmd.com/read/28718949/high-dosage-of-vitamin-d-regulates-the-energy-metabolism-and-increases-insulin-sensitivity-but-are-associated-with-high-levels-of-kidney-damage
#1
Rafael Calais Gaspar, José Diego Botezelli, Gabriel Keine Kuga, Vitor Rosetto Muñoz, Andressa Coope, Rodrigo Martins Pereira, Adelino Sanchez Ramos da Silva, Dennys Esper Cintra, Leandro Pereira de Moura, Eduardo Rochete Ropelle, José Rodrigo Pauli
Preclinical Research Metabolic disorders are responsible for more than 60% of all deaths worldwide. Calcitriol or vitamin D (vitD) deficiency is associated with a large proportion of these diseases is an important therapeutic target for exploration. This study evaluated the administration of high doses of vitD (3000 IU/kg) in obese and insulin-resistant C57BL/6J mice. Our results demonstrated that although high doses of vitD provided metabolic benefits such as increased insulin sensitivity and decreased body mass, this was associated with significant damage in the kidneys of obese mice...
July 18, 2017: Drug Development Research
https://www.readbyqxmd.com/read/28707063/liquid-chromatography-mass-spectrometry-methods-for-the-intracellular-determination-of-drugs-and-their-metabolites-a-focus-on-antiviral-drugs
#2
REVIEW
Pierre-André Billat, Franck Saint-Marcoux
Understanding the efficacy and/or toxicity of most drugs requires effective intracellular measurements of the drug and its metabolites. Nevertheless, the most common plasma marker of the biological effect of the drug is the area under the curve. Compared with drug determination in whole blood or urine, various difficulties occur in the development of analytical methods for intracellular measurements. We propose step-by-step guidelines to develop an analytical method exploring intracellular concentrations of antivirals and/or their metabolites...
July 13, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28699698/reduced-dosing-and-liability-in-methadone-maintenance-treatment-by-targeting-oestrogen-signal-for-morphine-addiction
#3
Yao-Chang Chiang, Ruey-Yun Wang, Chieh-Liang Huang, Shue-Hwa Chen, Wen-Jing Ho, Hsien-Yuan Lane, Ing-Kang Ho, Hwei-Ting Yang, Wen-Lung Ma
Methadone maintenance treatment (MMT) is the major tapering therapy for morphine addictive patients. There have gender differences reported in response to MMT. This study discovered that the estrogen-response element single nucleotide polymorphism (ERE-SNP; rs16974799, C/T) of cytochrome 2B6 gene (cyp2b6; methadone catabolic enzyme) responded differently to MMT dosing. Oestradiol was associated with high MMT dosing, high enantiomer (R- or S-) of 2-ethylidene-1,5-dimethyl-3,3-dipheny-pyrrolidine (EDDP; methadone metabolite) to methadone ratio and increased drug-seeking behaviour, implicating oestradiol-CYP-EDDP/methadone axis decreasing MMT efficacy...
July 12, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28689458/marmoset-pulmonary-cytochrome-p450-2f1-oxidizes-biphenyl-and-7-ethoxycoumarin-and-hepatic-human-p450-substrates
#4
Shotaro Uehara, Yasuhiro Uno, Toru Oshio, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
1. A potentially useful animal model for preclinical studies is the common marmoset (Callithrix jacchus). In this study, using reverse-transcription polymerase chain reaction from marmoset livers, we identified a novel cytochrome P450 (P450) 2F1 cDNA with an open reading frame of 1473 bp. 2. High sequence identities of 92-94% with primate P450 2F amino acid sequences were indicated by deduced amino acid sequences of P450 2F1 cDNA. Phylogenetic analysis indicates that marmoset P450 2F1 is more congruent with primate P450 2F forms than those of other species such as rodents...
July 8, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28687459/mouse-models-of-nonalcoholic-steatohepatitis-in-preclinical-drug-development
#5
REVIEW
Henrik H Hansen, Michael Feigh, Sanne S Veidal, Kristoffer T Rigbolt, Niels Vrang, Keld Fosgerau
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in the Western world. NAFLD is a complex spectrum of liver diseases ranging from benign hepatic steatosis to its more aggressive necroinflammatory manifestation, nonalcoholic steatohepatitis (NASH). NASH pathogenesis is multifactorial and risk factors are almost identical to those of the metabolic syndrome. This has prompted substantial efforts to identify novel drug therapies for correcting underlying metabolic deficits, and to prevent or alleviate hepatic fibrosis in NASH...
July 4, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28682065/discovery-of-clinical-candidate-4-2-5-amino-1h-pyrazol-4-yl-4-chlorophenoxy-5-chloro-2-fluoro-n-1-3-thiazol-4-ylbenzenesulfonamide-pf-05089771-design-and-optimization-of-diaryl-ether-aryl-sulfonamides-as-selective-inhibitors-of-nav1-7
#6
Nigel Alan Swain, Dave Batchelor, Serge Beaudoin, Bruce M Bechle, Paul A Bradley, Alan D Brown, Bruce Brown, Ken J Butcher, Richard P Butt, Mark L Chapman, Stephen Denton, David Ellis, Sebastien Galan, Stephen M Gaulier, Ben S Greener, Marcel J de Groot, Mel S Glossop, Ian K Gurrell, Jo Hannam, Matthew S Johnson, Zhixin Lin, Christopher J Markworth, Brian E Marron, David S Millan, Shoko Nakagawa, Andy Pike, David Printzenhoff, David J Rawson, Sarah J Ransley, Steven M Reister, Kosuke Sasaki, R Ian Storer, Paul Anthony Stupple, Christopher W West
A series of acidic diaryl ether heterocyclic sulfonamides that are potent and sub-type selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over non-metabolic routes of clearance, variable clearance in pre-clinical species and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics...
July 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28678794/ammonium-tetrathiomolybdate-following-ischemia-reperfusion-injury-chemistry-pharmacology-and-impact-of-a-new-class-of-sulfide-donor-in-preclinical-injury-models
#7
Alex Dyson, Felipe Dal-Pizzol, Giovanni Sabbatini, Anna B Lach, Federica Galfo, Juliano Dos Santos Cardoso, Bruna Pescador Mendonça, Iain Hargreaves, Bernardo Bollen Pinto, Daniel I Bromage, John F Martin, Kevin P Moore, Martin Feelisch, Mervyn Singer
BACKGROUND: Early revascularization of ischemic organs is key to improving outcomes, yet consequent reperfusion injury may be harmful. Reperfusion injury is largely attributed to excess mitochondrial production of reactive oxygen species (ROS). Sulfide inhibits mitochondria and reduces ROS production. Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility. METHODS AND FINDINGS: In vitro, ATTM releases sulfide in a time-, pH-, temperature-, and thiol-dependent manner...
July 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28675556/prospective-clinical-trials-to-investigate-clinical-and-molecular-biomarkers
#8
Stéphane Auvin, Lauren Walker, William Gallentine, Sergiusz Jozwiak, Mario Tombini, Graeme J Sills
Among clinical studies, randomized studies as well as well-designed observational studies are providing the highest quality data. In addition, these studies represent a good opportunity to examine biomarkers of ictogenesis and epileptogenesis. To date, no validated molecular or cellular biomarker exists for any aspect of epilepsy. We provide an overview of the inflammatory biomarkers under investigation in prospective clinical studies in epilepsy: proinflammatory cytokines in prolonged febrile seizure; High Mobility Group Box 1 (HMGB1) as a prognosis biomarker in epilepsy and the interaction between inflammation and metabolism, in particular, iron metabolism, in epilepsy...
July 2017: Epilepsia
https://www.readbyqxmd.com/read/28674030/s-nitrosoglutathione-reductase-gsnor-deficiency-confers-improved-survival-and-neurological-outcome-in-experimental-cerebral-malaria
#9
Robyn E Elphinstone, Rickvinder Besla, Eric A Shikatani, Ziyue Lu, Alfred Hausladen, Matthew Davies, Clinton S Robbins, Mansoor Husain, Jonathan S Stamler, Kevin C Kain
Artesunate remains the mainstay of treatment for cerebral malaria, but is less effective in later stages of disease when the host inflammatory response and blood brain barrier integrity dictate clinical outcomes. Nitric oxide (NO) is an important regulator of inflammation and microvascular integrity, and impaired NO bioactivity is associated with fatal outcomes in malaria. Endogenous NO bioactivity in mammals is largely mediated by S-nitrosothiols (SNOs). Based on these observations, we hypothesized that animals deficient in the SNO-metabolizing enzyme, S-nitrosoglutathione (GSNO) reductase (GSNOR), which exhibit enhanced S-nitrosylation, would have improved outcomes in a preclinical model of cerebral malaria...
July 3, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28668397/interleukin-6-c-ebp-%C3%AE-and-ppar-%C3%AE-expression-correlates-with-intramuscular-liposarcoma-growth-in-mice-the-impact-of-voluntary-physical-activity-levels
#10
Mohamad Assi, Moussa Kenawi, Mickaël Ropars, Amélie Rébillard
IL-6 is an axial cytokine overexpressed in cancer to promote growth and increase resistance to anti-cancer therapies. As the application of IL-6-targeting therapies are still limited, alternative non-aggressive and adjuvant approaches, like physical activity (PA) could be useful to reverse IL-6 effects. To get more insights into liposarcoma (LS) pathophysiology, we investigated potential molecular links between IL-6 and LS growth and we tested the impact of PA on such mechanism in an orthotopic model of intramuscular LS...
June 28, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28666894/pharmacological-comparison-of-traditional-and-non-traditional-cannabinoid-receptor-1-blockers-in-rodent-models-in-vivo
#11
Balázs Varga, Ferenc Kassai, György Szabó, Péter Kovács, János Fischer, István Gyertyán
Cannabinoid receptor 1 (CB1R) antagonists have been proven to be effective anti-obesity drugs; however, psychiatric side effects have halted their pharmaceutical development worldwide. Despite the emergence of next generation CB1R blockers, a preclinical head to head comparison of the anti-obesity and psychiatric side effect profiles of the key compounds has not been performed. Here, we compared classical CB1R antagonists (rimonabant, taranabant, otenabant, ibipinabant, and surinabant) and non-traditional CB1R blockers (the partial agonist O-1269, the neutral antagonists VCHSR and LH-21 and the peripherally acting inverse agonist JD-5037) using an in vivo screening cascade...
June 27, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28663873/autofluorescence-imaging-captures-heterogeneous-drug-response-differences-between-2d-and-3d-breast-cancer-cultures
#12
T M Cannon, A T Shah, M C Skala
Two-photon microscopy of cellular autofluorescence intensity and lifetime (optical metabolic imaging, or OMI) is a promising tool for preclinical drug development. OMI, which exploits the endogenous fluorescence from the metabolic coenzymes NAD(P)H and FAD, is sensitive to changes in cell metabolism produced by drug treatment. Previous studies have shown that drug response, genetic expression, cell-cell communication, and cell signaling in 3D culture match those of the original in vivo tumor, but not those of 2D culture...
March 1, 2017: Biomedical Optics Express
https://www.readbyqxmd.com/read/28663375/sexually-dimorphic-skeletal-muscle-and-cardiac-dysfunction-in-a-mouse-model-of-limb-girdle-muscular-dystrophy-2i
#13
Joseph W Maricelli, Denali R Kagel, Yemeserach M Bishaw, O Lynne Nelson, David C Lin, Buel D Rodgers
The fukutin-related protein P448L mutant mouse replicates pathologies common to limb-girdle muscular dystrophy 2i (LGMD2i) and is a strong candidate for relevant drug screening studies. Because striated muscle function remains relatively uncharacterized in this mouse, we sought to identify metabolic, functional and histological metrics of exercise and cardiac performance by quantifying voluntary exercise on running wheels, forced exercise on respiratory treadmills and cardiac output with echocardiography and isoproterenol stress tests...
June 29, 2017: Journal of Applied Physiology
https://www.readbyqxmd.com/read/28659616/a-novel-humanized-mouse-lacking-murine-p450-oxidoreductase-for-studying-human-drug-metabolism
#14
Mercedes Barzi, Francis P Pankowicz, Barry Zorman, Xing Liu, Xavier Legras, Diane Yang, Malgorzata Borowiak, Beatrice Bissig-Choisat, Pavel Sumazin, Feng Li, Karl-Dimiter Bissig
Only one out of 10 drugs in development passes clinical trials. Many fail because experimental animal models poorly predict human xenobiotic metabolism. Human liver chimeric mice are a step forward in this regard, as the human hepatocytes in chimeric livers generate human metabolites, but the remaining murine hepatocytes contain an expanded set of P450 cytochromes that form the major class of drug-metabolizing enzymes. We therefore generated a conditional knock-out of the NADPH-P450 oxidoreductase (Por) gene combined with Il2rg (- /-) /Rag2 (- /-) /Fah (- /-) (PIRF) mice...
June 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28659169/the-novel-compound-pbt434-prevents-iron-mediated-neurodegeneration-and-alpha-synuclein-toxicity-in-multiple-models-of-parkinson-s-disease
#15
David I Finkelstein, Jessica L Billings, Paul A Adlard, Scott Ayton, Amelia Sedjahtera, Colin L Masters, Simon Wilkins, David M Shackleford, Susan A Charman, Wojciech Bal, Izabela A Zawisza, Ewa Kurowska, Andrew L Gundlach, Sheri Ma, Ashley I Bush, Dominic J Hare, Philip A Doble, Simon Crawford, Elisabeth Cl Gautier, Jack Parsons, Penny Huggins, Kevin J Barnham, Robert A Cherny
Elevated iron in the SNpc may play a key role in Parkinson's disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions...
June 28, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28656481/heart-failure-with-preserved-ejection-fraction-and-future-pharmacological-strategies-a-glance-in-the-crystal-ball
#16
REVIEW
Carsten Tschöpe, Sophie Van Linthout, Behrouz Kherad
PURPOSE OF REVIEW: The current definition of heart failure is mainly based on an inappropriate measure of cardiac function, i.e., left ventricular ejection fraction (LVEF). The initial sole entity, heart failure with reduced ejection fraction (HFrEF, LVEF <40%), was complemented by the addition of heart failure with preserved ejection fraction (HFpEF, LVEF ≥50%) and most recently, heart failure with mid-range ejection fraction (HFmrEF, LVEF 40-49%). Initially, HFpEF was believed to be a purely left ventricular diastolic dysfunction...
August 2017: Current Cardiology Reports
https://www.readbyqxmd.com/read/28656091/a-review-of-the-effects-of-berberis-vulgaris-and-its-major-component-berberine-in-metabolic-syndrome
#17
REVIEW
Jamshid Tabeshpour, Mohsen Imenshahidi, Hossein Hosseinzadeh
Metabolic syndrome (MetS), characterized by a cluster of metabolic abnormalities including hypertension, obesity, type 2 diabetes mellitus (T2DM) and dyslipidemia, is a well-known cardiovascular risk factor (CVRF). Cardiovascular disease (CVD) represents a massive healthcare burden worldwide. In recent years, with regard to the adverse effects of synthetic drugs, increasing attention has been paid by researchers to herbal medicines for a variety of disorders such as CVD. A large body of literature supports different pharmacological actions of Berberis vulgaris (B...
May 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28636311/insights-into-integrated-lead-generation-and-target-identification-in-malaria-and-tuberculosis-drug-discovery
#18
John Okombo, Kelly Chibale
New, safe and effective drugs are urgently needed to treat and control malaria and tuberculosis, which affect millions of people annually. However, financial return on investment in the poor settings where these diseases are mostly prevalent is very minimal to support market-driven drug discovery and development. Moreover, the imminent loss of therapeutic lifespan of existing therapies due to evolution and spread of drug resistance further compounds the urgency to identify novel effective drugs. However, the advent of new public-private partnerships focused on tropical diseases and the recent release of large data sets by pharmaceutical companies on antimalarial and antituberculosis compounds derived from phenotypic whole cell high throughput screening have spurred renewed interest and opened new frontiers in malaria and tuberculosis drug discovery...
June 21, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28629389/cancer-chemoprevention-through-dietary-flavonoids-what-s-limiting
#19
REVIEW
Haneen Amawi, Charles R Ashby, Amit K Tiwari
Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cancers via a multitude of mechanisms. However, the clinical use of flavonoids is limited due to challenges associated with their effective use, including (1) the isolation and purification of flavonoids from their natural resources; (2) demonstration of the effects of flavonoids in reducing the risk of certain cancer, in tandem with the cost and time needed for epidemiological studies, and (3) numerous pharmacokinetic challenges (e...
June 19, 2017: Chinese Journal of Cancer
https://www.readbyqxmd.com/read/28592260/recent-advances-in-the-use-of-pi3k-inhibitors-for-glioblastoma-multiforme-current-preclinical-and-clinical-development
#20
REVIEW
Hua-Fu Zhao, Jing Wang, Wei Shao, Chang-Peng Wu, Zhong-Ping Chen, Shing-Shun Tony To, Wei-Ping Li
Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism...
June 7, 2017: Molecular Cancer
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