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imatinib metabolism

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https://www.readbyqxmd.com/read/29806063/changes-in-estimated-glomerular-filtration-rate-in-chronic-myeloid-leukemia-patients-treated-front-line-with-available-tkis-and-correlation-with-cardiovascular-events
#1
Matteo Molica, Emilia Scalzulli, Gioia Colafigli, Danilo Alunni Fegatelli, Fulvio Massaro, Roberto Latagliata, Robin Foà, Massimo Breccia
We investigated the median estimated glomerular filtration rate (eGFR) changes in chronic myeloid leukemia (CML) patients treated front line with tyrosine kinase inhibitors (TKIs). A large cohort of 397 patients-320 treated front line with imatinib, 25 with dasatinib, and 53 with nilotinib-was retrospectively analyzed at a single institution. The eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation for all patients at baseline and then at 6 and 12 months, and at the last follow-up...
May 27, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29770723/the-impact-of-azole-antifungal-drugs-on-imatinib-metabolism-in-human-liver-microsomes
#2
Xingxian Luo, Taifeng Li, Ze Yu, Xuecai Xue, Haiyang Zhao, Na Li, Liping Ma, Changqing Yang, Lin Huanglin, Wangyu Feng
1. Imatinib is widely used for the treatment of hematologic malignancies. It is common that imatinib is clinically co-prescribed with azole antifungal agents since these patients are more prone to invasive antifungal infection. The present study was to investigate the effects of azole antifungal drugs, including ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole on imatinib metabolism. 2. The main metabolites, 1-OH midazolam and N-desmethyl imatinib, were determined in the absence and in the presence of various levels of ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole...
May 17, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29749314/glycolysis-inhibition-as-a-strategy-for-hepatocellular-carcinoma-treatment
#3
Andreia Alves, Ana Catarina Mamede, Marco Alves, Pedro F Oliveira, Sandra Moreira Rocha, Filomena Botelho, Claudio Jorge Maia
Hepatocellular carcinoma (HCC) is the most frequently detected primary malignant liver tumor, representing a worldwide public health problem due to its high morbidity and mortality rates. The HCC is commonly detected in advanced stage, precluding the use of treatments with curative intent. For this reason, it is crucial to find effective therapies for HCC. Cancer cells have a high dependence of glycolysis for ATP production, especially under hypoxic environment. Such dependence provides a reliable possible strategy to specifically target cancer cells based on the inhibition of glycolysis...
April 30, 2018: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/29741432/inter-individual-variation-in-imatinib-disposition-any-role-for-prevalent-variants-of-cyp1a2-cyp2c8-cyp2c9-and-cyp3a5-in-nigerian-cml-patients
#4
Ayorinde Adehin, Babatunde A Adeagbo, Martin A Kennedy, Oluseye O Bolaji, Tiwalade A Olugbade, Rahman A Bolarinwa, Muheez A Durosinmi
Imatinib has been successful in the management of chronic myeloid leukemia (CML) but some patients experience adverse reactions or develop resistance to its use. The roles of some polymorphisms in genes encoding enzymes critical for the biotransformation of imatinib have been previously examined. This study, hence, evaluated some other unstudied functionally significant polymorphisms in CYP1A2, CYP2C8, CYP2C9, and CYP3A5. Trough imatinib blood levels and genotypes were determined in 42 CML patients by an HPLC-UV technique and a Sequenom iPLEX assay, respectively...
May 9, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29717168/allosteric-modulation-of-the-farnesoid-x-receptor-by-a-small-molecule
#5
Matthias Gabler, Jan Kramer, Jurema Schmidt, Julius Pollinger, Julia Weber, Astrid Kaiser, Frank Löhr, Ewgenij Proschak, Manfred Schubert-Zsilavecz, Daniel Merk
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells...
May 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29643676/discordant-primary-resistance-to-imatinib-mesylate-in-the-same-individual-and-splenic-involvement-in-recurring-gastric-gastrointestinal-stromal-tumors-assessment-by-fluorodeoxyglucose-positron-emission-tomography-computed-tomography
#6
Preeti Fargose, Sandip Basu
Discordant primary resistance and response of the metastatic lesions in the same individual coupled with splenic involvement in gastrointestinal stromal tumors (GISTs) are relatively uncommon. We herein report such a case of recurring GIST of the stomach that presented with the involvement of spleen with 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) imaging documentation. Ultrasonography-guided fine needle aspiration cytology from the splenic and paravesical lesions demonstrated metastatic spindle cell tumor consistent with diagnosis of metastasis from GIST of the stomach...
April 2018: Indian Journal of Nuclear Medicine: IJNM: the Official Journal of the Society of Nuclear Medicine, India
https://www.readbyqxmd.com/read/29615437/refinement-of-in-vitro-methods-for-identification-of-aldehyde-oxidase-substrates-reveals-metabolites-of-kinase-inhibitors
#7
Ryan A Dick
To identify aldehyde oxidase (AO) substrates, an assay procedure was developed that leverages the capabilities of high-resolution mass spectrometry to simultaneously monitor parent loss and formation of hydroxylated metabolite over time in incubations with liver cytosol. By incorporating metabolite monitoring, false positives resulting from metabolism by other cytosolic enzymes or processes were decreased. A diverse set of 34 kinase inhibitors containing AO-substrate motifs was screened, and 35% of the compounds were identified as human AO substrates...
June 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29615094/heterogeneity-in-the-in-vitro-susceptibility-of-loa-loa-microfilariae-to-drugs-commonly-used-in-parasitological-infections
#8
Abdel J Njouendou, Fanny F Fombad, Maeghan O'Neill, Denis Zofou, Chuck Nutting, Patrick C Ndongmo, Arnaud J Kengne-Ouafo, Timothy G Geary, Charles D Mackenzie, Samuel Wanji
BACKGROUND: Co-infection with loiasis remains a potential problem in control programs targeting filarial infections. The effects of many anti-parasitic drugs often administered to Loa loa infected people are not well documented. This study compared the in vitro activity of several of these drugs on the viability of L. loa microfilariae (mf). METHODS: Human strain L. loa mf were isolated from baboon blood using iso-osmotic Percoll gradient, and cultured in RPMI 1640/10% FBS with antimalarial drugs (mefloquine, amodiaquine, artesunate, chloroquine and quinine), anthelmintics (ivermectin, praziquantel, flubendazole and its reduced and hydrolyzed metabolites), two potential trypanocidal agents (fexinidazole and Scynexis-7158) and the anticancer drug imatinib...
April 4, 2018: Parasites & Vectors
https://www.readbyqxmd.com/read/29551130/acquired-resistance-to-drugs-targeting-tyrosine-kinases
#9
Steven A Rosenzweig
Resistance to chemotherapeutic drugs exemplifies the greatest hindrance to effective treatment of cancer patients. The molecular mechanisms responsible have been investigated for over 50 years and have revealed the lack of a single cause, but instead, multiple mechanisms including induced expression of membrane transporters that pump drugs out of cells (multidrug resistance (MDR) phenotype), changes in the glutathione system, and altered metabolism. Treatment of cancer patients/cancer cells with chemotherapeutic agents and/or molecularly targeted drugs is accompanied by acquisition of resistance to the treatment administered...
2018: Advances in Cancer Research
https://www.readbyqxmd.com/read/29506493/mixed-response-on-regorafenib-treatment-for-gist-gastro-intestinal-stromal-tumor-according-to-18-f-fdg-pet-ct
#10
Donatienne Van Weehaeghe, Olivier Gheysens, Vincent Vandecaveye, Patrick Schöffski, Koen Van Laere, Christophe M Deroose
BACKGROUND: Gastro-intestinal stromal tumors (GISTs) are very rare tumors of the gastro-intestinal tract, originating from the interstitial cells of Cajal or a common cell precursor which both express type III tyrosine kinase receptors. Regorafenib is an oral multi-kinase inhibitor used to treat gastro-intestinal stromal tumors. To our knowledge this is the first case in literature to show the response of regorafenib on PET. CASE PRESENTATION: A 37-year-old male with lower abdominal pain and weight loss was referred to our hospital...
March 5, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29454474/cardiovascular-pulmonary-and-metabolic-toxicities-complicating-tyrosine-kinase-inhibitor-therapy-in-chronic-myeloid-leukemia-strategies-for-monitoring-detecting-and-managing
#11
REVIEW
Bruno C Medeiros, Jennifer Possick, Michael Fradley
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, the incidence of which increases with age. Tyrosine kinase inhibitors (TKIs) are the mainstay of CML treatment, including imatinib, nilotinib, dasatinib, bosutinib, and ponatinib. Beyond matching patient disease profiles with TKI specificity, differences in the efficacy and toxicity profiles and a patient's comorbid risk factors should be considered when selecting the most appropriate agent. Our objectives are to review the incidence and severity of cardiovascular, metabolic, and pulmonary disorders associated with these TKIs, highlighting differences in adverse event profiles, suggested risk-mitigation strategies, and guidance for TKI selection in different settings...
February 3, 2018: Blood Reviews
https://www.readbyqxmd.com/read/29404396/auto-commentary-on-targeting-mitochondrial-oxidative-phosphorylation-eradicates-therapy-resistant-chronic-myeloid-leukemia-stem-cells
#12
Lucie de Beauchamp, Pablo Baquero, Elodie M Kuntz, Eyal Gottlieb, G Vignir Helgason
We have recently uncovered an abnormal increase in mitochondrial oxidative metabolism in therapy-resistant chronic myeloid leukaemia stem cells (LSCs). By simultaneously disrupting mitochondrial respiration and inhibiting BCR-ABL kinase activity using the antibiotic tigecycline and imatinib respectively, we effectively eradicated LSCs and prevented disease relapse in pre-clinical animal models.
2018: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29315500/long-term-outcome-of-dasatinib-first-line-treatment-in-gastrointestinal-stromal-tumor-a-multicenter-2-stage-phase-2-trial-swiss-group-for-clinical-cancer-research-56-07
#13
Michael Montemurro, Angela Cioffi, Julien Dômont, Piotr Rutkowski, Arnaud D Roth, Roger von Moos, Roman Inauen, Maud Toulmonde, Roger O Burkhard, Claudio Knuesli, Sebastian Bauer, Philippe Cassier, Heike Schwarb, Axel Le Cesne, Dieter Koeberle, Daniela Bärtschi, Daniel Dietrich, Christine Biaggi, John Prior, Serge Leyvraz
BACKGROUND: Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with gastrointestinal stromal tumors (GISTs), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of BCR-ABL, KIT, and SRC family kinases as well as imatinib-resistant cells. In GISTs, response evaluation is routinely done using computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography coupled to CT (FDG-PET/CT) for early response assessment and outcome prediction...
April 1, 2018: Cancer
https://www.readbyqxmd.com/read/29246941/mitochondrial-inhibition-augments-the-efficacy-of-imatinib-by-resetting-the-metabolic-phenotype-of-gastrointestinal-stromal-tumor
#14
Gerardo A Vitiello, Benjamin D Medina, Shan Zeng, Timothy G Bowler, Jennifer Q Zhang, Jennifer K Loo, Nesteene J Param, Mengyuan Liu, Alec J Moral, Julia N Zhao, Ferdinand Rossi, Cristina R Antonescu, Vinod P Balachandran, Justin R Cross, Ronald P DeMatteo
Purpose: Imatinib dramatically reduces gastrointestinal stromal tumor (GIST)18 F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown. Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered KitV558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity...
February 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29166334/gastrointestinal-stromal-tumor-of-the-prostate-staging-and-evaluation-of-response-to-therapy-with-18f-fdg-pet-ct
#15
Yazan Z Alabed
A 49-year-old man presented for routine general physical examination was found with an enlarged prostate gland without associated symptoms. Ultrasound followed by computed tomography (CT) of abdomen and pelvis confirmed a markedly enlarged heterogeneous prostate gland. Subsequently, a staging flourine-18 fluorodeoxyglucose (F-FDG) positron emission tomography (PET/CT) scan revealed intensely FDG-avid mass involving the prostate, which was biopsied as gastrointestinal stromal tumor (GIST). The patient was treated with imatinib and a follow-up PET/CT scan showed complete metabolic response...
January 2018: Clinical Nuclear Medicine
https://www.readbyqxmd.com/read/29138287/clopidogrel-carboxylic-acid-glucuronidation-is-mediated-mainly-by-ugt2b7-ugt2b4-and-ugt2b17-implications-for-pharmacogenetics-and-drug-drug-interactions
#16
Helinä Kahma, Anne M Filppula, Mikko Neuvonen, E Katriina Tarkiainen, Aleksi Tornio, Mikko T Holmberg, Matti K Itkonen, Moshe Finel, Pertti J Neuvonen, Mikko Niemi, Janne T Backman
The antiplatelet drug clopidogrel is metabolized to an acyl- β -d-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl- β -d-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLMs and HIMs, respectively) and selected human recombinant UGTs based on preliminary screening. The effects of relevant UGT polymorphisms on the pharmacokinetics of clopidogrel were evaluated in 106 healthy volunteers...
February 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29121435/altered-intracellular-signaling-by-imatinib-increases-the-anti-cancer-effects-of-tyrosine-kinase-inhibitors-in-chronic-myelogenous-leukemia-cells
#17
Takuya Hirao, Masashi Yamaguchi, Megumi Kikuya, Hiroji Chibana, Kousei Ito, Shigeki Aoki
Tyrosine kinase inhibitors (TKI), including imatinib (IM), improve the outcome of CML therapy. However, TKI treatment is long-term and can induce resistance to TKI, which often leads to a poor clinical outcome in CML patients. Here, we examined the effect of continuous IM exposure on intracellular energy metabolism in K562 cells, a human Philadelphia chromosome-positive CML cell line, and its subsequent sensitivity to anti-cancer agents. Contrary to our expectations, we found that continuous IM exposure increased sensitivity to TKI...
January 2018: Cancer Science
https://www.readbyqxmd.com/read/29115640/off%C3%A2-target-effect-of-imatinib-and-nilotinib-on-human-vitamin-d3-metabolism
#18
Lysann Kroschwald, Meinolf Suttorp, Josephine Tabea Tauer, Nick Zimmermann, Claudia Günther, Andrea Bauer
Prolonged treatment with tyrosine kinase inhibitors (TKI) including imatinib (IMA) or nilotinib (NIL), induces severe disturbances of bone metabolism in patients with chronic myeloid leukaemia. As vitamin D3 (VD3) is involved in the complex cycle of bone remodelling, the present study investigated in vitro, the influence of IMA and NIL on VD3 metabolism i) in HaCaT cells and ii) in cultured outer root sheath keratinocytes (ORS‑KC) from hair follicles of IMA treated children. Cells were incubated in the presence of IMA or NIL...
January 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28970330/early-evaluation-of-response-using-18-f-fdg-pet-influences-management-in-gastrointestinal-stromal-tumor-patients-treated-with-neoadjuvant-imatinib
#19
Sheima Farag, Lioe-Fee de Geus-Oei, Winette T van der Graaf, Frits van Coevorden, Dirk Grunhagen, Anna K L Reyners, Pieter A Boonstra, Ingrid Desar, Hans Gelderblom, Neeltje Steeghs
18 F-FDG PET has previously been proven effective as an early way to evaluate the response of gastrointestinal stromal tumors (GISTs) to imatinib treatment. However, it is unclear whether early evaluation of response affects treatment decisions in GIST patients treated with neoadjuvant intent. Methods: We retrospectively scored changes in management based on early evaluation of response by 18 F-FDG PET in patients in the Dutch GIST registry treated with neoadjuvant imatinib. Results: Seventy 18 F-FDG PET scans were obtained for 63 GIST patients to evaluate for an early response to neoadjuvant imatinib...
February 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28920959/targeting-mitochondrial-oxidative-phosphorylation-eradicates-therapy-resistant-chronic-myeloid-leukemia-stem-cells
#20
Elodie M Kuntz, Pablo Baquero, Alison M Michie, Karen Dunn, Saverio Tardito, Tessa L Holyoake, G Vignir Helgason, Eyal Gottlieb
Treatment of chronic myeloid leukemia (CML) with imatinib mesylate and other second- and/or third-generation c-Abl-specific tyrosine kinase inhibitors (TKIs) has substantially extended patient survival. However, TKIs primarily target differentiated cells and do not eliminate leukemic stem cells (LSCs). Therefore, targeting minimal residual disease to prevent acquired resistance and/or disease relapse requires identification of new LSC-selective target(s) that can be exploited therapeutically. Considering that malignant transformation involves cellular metabolic changes, which may in turn render the transformed cells susceptible to specific assaults in a selective manner, we searched for such vulnerabilities in CML LSCs...
October 2017: Nature Medicine
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