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drug metabolism, preclinical

Nora Freyer, Selina Greuel, Fanny Knöspel, Florian Gerstmann, Lisa Storch, Georg Damm, Daniel Seehofer, Jennifer Foster Harris, Rashi Iyer, Frank Schubert, Katrin Zeilinger
The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP ( p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP ( p < 0...
March 15, 2018: Bioengineering
Natthakan Thongon, Chiara Zucal, Vito Giuseppe D'Agostino, Toma Tebaldi, Silvia Ravera, Federica Zamporlini, Francesco Piacente, Ruxanda Moschoi, Nadia Raffaelli, Alessandro Quattrone, Alessio Nencioni, Jean-Francois Peyron, Alessandro Provenzani
Background: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods: We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms...
2018: Cancer & Metabolism
Alberto M Martelli, Francesca Buontempo, James A McCubrey
Mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. mTORC1 and mTORC2 play key physiological roles as they control anabolic and catabolic processes in response to external cues in a variety of tissues and organs. However, mTORC1 and mTORC2 activities are deregulated in widespread human diseases, including cancer. Cancer cells take advantage of mTOR oncogenic signaling to drive their proliferation, survival, metabolic transformation, and metastatic potential...
March 15, 2018: Clinical Science (1979-)
Sandra Jordaan, Olusiji A Akinrinmade, Thomas Nachreiner, Christian Cremer, Krupa Naran, Shivan Chetty, Stefan Barth
Targeted cancer therapy includes, amongst others, antibody-based delivery of toxic payloads to selectively eliminate tumor cells. This payload can be either a synthetic small molecule drug composing an antibody-drug conjugate (ADC) or a cytotoxic protein composing an immunotoxin (IT). Non-human cytotoxic proteins, while potent, have limited clinical efficacy due to their immunogenicity and potential off-target toxicity. Humanization of the cytotoxic payload is essential and requires harnessing of potent apoptosis-inducing human proteins with conditional activity, which rely on targeted delivery to contact their substrate...
March 5, 2018: Biomedicines
Bryan F Burkey, Niel C Hoglen, Philip Inskeep, Margaret Wyman, Thomas E Hughes, James E Vath
Methionine aminopeptidase 2 (MetAP2) inhibition is a promising approach to treating diabetes, obesity, and associated metabolic disorders. Beloranib, a MetAP2 inhibitor previously investigated for treatment of Prader-Willi syndrome, was associated with venous thrombotic adverse events likely resulting from drug effects on vascular endothelial cells (ECs). Here, we report the pharmacological characterization of ZGN-1061, a novel MetAP2 inhibitor being investigated for treatment of diabetes and obesity. Four weeks of subcutaneous administration of ZGN-1061 to diet-induced obese (DIO) insulin-resistant mice produced a 25% reduction in body weight, primarily due to reduced fat mass, that was comparable to beloranib...
February 28, 2018: Journal of Pharmacology and Experimental Therapeutics
Raeeka Khamari, Anne Trinh, Pierre Elliott Gabert, Paola Corazao-Rozas, Samuel Riveros-Cruz, Stephane Balayssac, Myriam Malet-Martino, Salim Dekiouk, Marie Joncquel Chevalier Curt, Patrice Maboudou, Guillaume Garçon, Laura Ravasi, Pierre Guerreschi, Laurent Mortier, Bruno Quesnel, Philippe Marchetti, Jerome Kluza
Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase...
February 27, 2018: Cell Death & Disease
Ashok K Singh, Umesh Kumar, Vinit Raj, Vimal Maurya, Dinesh Kumar, Biswanath Maity, Anand Prakash, Arnab De, Amalesh Samanta, Sudipta Saha
AIMS: In quest for alternative drugs to the well known paullones, recently we synthesized novel paullone-like scaffold, 5H-benzo [2,3][1,4]oxazepino[5,6-b]indoles, where compounds 13a (Ta) and 14a (Tb) attenuated liver cancer specific Hep-G2 cells in vitro and formed stable binding complex with IL-6. Henceforth, we hypothesized that this action is probably due to the blockade of IL-6 mediated JAK2/STAT3 signaling cascade. Other objective was to explore the ability of FOIs to regulate metabolic perturbations during hepatocellular carcinoma (HCC)...
February 24, 2018: Life Sciences
Eita Sasaki, Tsuyoshi Yokoi
Several drugs have been withdrawn from the market or restricted to avoid unexpected adverse outcomes. Drug-induced liver injury (DILI) is a serious issue for drug development. Among DILIs, idiosyncratic DILIs have been a serious problem in drug development and clinical uses. Idiosyncratic DILI is most often unrelated to pharmacological effects or the dosing amount of a drug. The number of drugs that cause idiosyncratic DILI continue to grow in part because no practical preclinical tests have emerged that can identify drug candidates with the potential for developing idiosyncratic DILIs...
2018: Journal of Toxicological Sciences
Karla Pelivan, Lisa M Frensemeier, Uwe Karst, Gunda Koellensperger, Petra Heffeter, Bernhard K Keppler, Christian R Kowol
Clinical failure of novel drugs is often related to their rapid metabolism and excretion. This highlights the importance of elucidation of their pharmacokinetic profile already at the preclinical stage of drug development. Triapine, the most prominent representative of α-N-heterocyclic thiosemicarbazones, was investigated in more than 30 clinical phase I/II trials, but the results against solid tumors were disappointing. Recent investigations from our group suggested that this is, at least partially, based on the fast metabolism and excretion...
February 23, 2018: Analytical and Bioanalytical Chemistry
Chuantao Zha, Wenjia Deng, Yan Fu, Shuai Tang, Xiaojing Lan, Yan Ye, Yi Su, Lei Jiang, Yi Chen, Ying Huang, Jian Ding, Meiyu Geng, Min Huang, Huixin Wan
CDK4/6 pathway is an attractive chemotherapeutic target for antitumor drug discovery and development. Herein, we reported the structure-based design and synthesis of a series of novel tetrahydronaphthyridine analogues as selective CDK4/6 inhibitors. Compound 5 was identified as a hit and then systematically structure optimization study was conducted. These efforts led to compound 28, which exhibited excellent in vitro potencies against CDK4/6 enzymatic activity with high selectivity over CDK1, and against Colo-205 cell growth...
February 12, 2018: European Journal of Medicinal Chemistry
Thea Kristin Våtsveen, Marit Renée Myhre, Chloé Beate Steen, Sébastien Wälchli, Ole Christian Lingjærde, Baoyan Bai, Pierre Dillard, Theodossis A Theodossiou, Toril Holien, Anders Sundan, Else Marit Inderberg, Erlend B Smeland, June Helen Myklebust, Morten P Oksvold
BACKGROUND: Although chemo-immunotherapy has led to an improved overall survival for most B-cell lymphoma types, relapsed and refractory disease remains a challenge. The malaria drug artesunate has previously been identified as a growth suppressor in some cancer types and was tested as a new treatment option in B-cell lymphoma. METHODS: We included artesunate in a cancer sensitivity drug screen in B lymphoma cell lines. The preclinical properties of artesunate was tested as single agent in vitro in 18 B-cell lymphoma cell lines representing different histologies and in vivo in an aggressive B-cell lymphoma xenograft model, using NSG mice...
February 20, 2018: Journal of Hematology & Oncology
Panagiotis Koliou, Vasilios Karavasilis, Maria Theochari, Seth M Pollack, Robin L Jones, Khin Thway
Eribulin mesylate is a synthetic derivative of halichondrin B isolated from a marine sponge. Its mechanism of action is through microtubule inhibition, which is different from that of taxanes. Eribulin has been approved for the treatment of metastatic breast cancer and more recently for non-operable or metastatic liposarcoma in patients who have received prior anthracycline chemotherapy. The major side effects of eribulin are bone marrow suppression including neutropenia, leukopenia, anemia, and fatigue/weakness, which can be well managed...
2018: Cancer Management and Research
Dominik Linz, Mathias Hohl, Adrian D Elliott, Dennis H Lau, Felix Mahfoud, Murray D Esler, Prashanthan Sanders, Michael Böhm
Renal afferent and efferent sympathetic nerves are involved in the regulation of blood pressure and have a pathophysiological role in hypertension. Additionally, several conditions that frequently coexist with hypertension, such as heart failure, obstructive sleep apnea, atrial fibrillation, renal dysfunction, and metabolic syndrome, demonstrate enhanced sympathetic activity. Renal denervation (RDN) is an approach to reduce renal and whole body sympathetic activation. Experimental models indicate that RDN has the potential to lower blood pressure and prevent cardio-renal remodeling in chronic diseases associated with enhanced sympathetic activation...
February 10, 2018: Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society
Makoto Suzuki
For research and development (R&D) of new drugs, animal experimentation is indispensable, and research institutes, pharmaceutical companies, or contract research organizations routinely conduct preclinical studies of efficacy, safety, or metabolism using laboratory animals. However, animal experimentation entails some organizational risks. One is the suspension of R&D of a new drug, because in the course of clinical studies it becomes apparent that the drug has limited efficacy, unexpected side effects, and/or unexpected metabolites...
2018: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
Rami Al Batran, Malak Almutairi, John R Ussher
Glucagon-like peptide-1 receptor (GLP-1R) agonists are frequently used to improve glycemia in patients with type 2 diabetes (T2D). Recent data from cardiovascular outcomes trials for the GLP-1R agonists, liraglutide and semaglutide, have also demonstrated significant reductions in death rates from cardiovascular causes in patients with T2D. As cardiovascular death is the number one cause of death in patients with T2D, understanding the mechanisms by which GLP-1R agonists such as liraglutide and semaglutide improve cardiac function is essential...
February 2018: Peptides
Yan Xin, Winnie Weng, Bernard P Murray, Eugene J Eisenberg, Jason W Chien, John Ling, Jeffrey A Silverman
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5...
February 7, 2018: Journal of Clinical Pharmacology
Miren Ettcheto, Elena Sánchez-López, Yaiza Gómez-Mínguez, Henrry Cabrera, Oriol Busquets, Carlos Beas-Zarate, Maria Luisa García, Eva Carro, Gemma Casadesus, Carme Auladell, Manuel Vázquez Carrera, Jaume Folch, Antoni Camins
There is growing evidence that obesity associated with type 2 diabetes mellitus (T2DM) and aging are risk factors for the development of Alzheimer's disease (AD). However, the molecular mechanisms through which obesity interacts with β-amyloid (Aβ) to promote cognitive decline remains poorly understood. Memantine (MEM), a N-methyl-D-aspartate receptor antagonist, is currently used for the treatment of AD. Nonetheless, few studies have reported its effects on genetic preclinical models of this neurodegenerative disease exacerbated with high-fat diet (HFD)-induced obesity...
February 5, 2018: Molecular Neurobiology
Guillaume Wettstein, Jean-Michel Luccarini, Laurence Poekes, Patrick Faye, Francine Kupkowski, Vanessa Adarbes, Evelyne Defrêne, Céline Estivalet, Xavier Gawronski, Ingrid Jantzen, Alain Philippot, Julien Tessier, Pascale Tuyaa-Boustugue, Fiona Oakley, Derek A Mann, Isabelle Leclercq, Sven Francque, Irena Konstantinova, Pierre Broqua, Jean-Louis Junien
IVA337 is a pan-peroxisome proliferator-activated receptor (PPAR) agonist with moderate and well-balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis...
August 2017: Hepatology communications
Agnese Fiori, Vincenzo Terlizzi, Heiner Kremer, Julian Gebauer, Hans-Peter Hammes, Martin C Harmsen, Karen Bieback
Diabetic retinopathy (DR) is a multifactorial microvascular disease induced by hyperglycemia and subsequent metabolic abnormalities. The resulting cell stress causes a sequela of events that ultimately can lead to severe vision impairment and blindness. The early stages are characterized by activation of glia and loss of pericytes, endothelial cells (EC) and neuronal cells. The integrity of the retinal microvasculature becomes affected, and, as a possible late response, macular edema may develop as a common reason for vision loss in patients with non-proliferative DR...
February 2, 2018: Immunobiology
Ran-Ran Zhang, Yun-Wen Zheng, Bin Li, Yun-Zhong Nie, Yasuharu Ueno, Tomonori Tsuchida, Hideki Taniguchi
BACKGROUND: Mature human hepatocytes are critical in preclinical research and therapy for liver disease, but are difficult to manipulate and expand in vitro. Hepatic stem cells (HpSCs) may be an alternative source of functional hepatocytes for cell therapy and disease modeling. Since these cells play an import role in regenerative medicine, the precise characterization that determines specific markers used to isolate these cells as well as whether they contribute to liver regeneration still remain to be shown...
February 5, 2018: Stem Cell Research & Therapy
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