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https://www.readbyqxmd.com/read/29222244/cardiovascular-care-of-patients-with-chronic-myeloid-leukemia-cml-on-tyrosine-kinase-inhibitor-tki-therapy
#1
REVIEW
Mary C Barber, Michael J Mauro, Javid Moslehi
Cardiovascular (CV) health has emerged as an important consideration in patients with chronic myeloid leukemia (CML) because of improved prognosis. Indeed, the success of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has increased the focus on survivorship and late toxicity in oncological care. Survivorship issues in this population include CV disease prevention, given its prevalence in the general population. The introduction of BCR-ABL1 TKIs represented a unique concept of indefinite cancer therapy, only recently evolving to include "treatment-free remission...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29220734/high-throughput-routine-determination-of-17-tyrosine-kinase-inhibitors-by-lc-ms-ms
#2
Camille Merienne, Marine Rousset, Dominique Ducint, Nadège Castaing, Karine Titier, Mathieu Molimard, Stéphane Bouchet
Several studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKI) can improve their benefit in cancer. An analytical tool has been developed in order to quantify 17 tyrosine kinase inhibitors and 2 metabolites in human plasma (afatinib, axitinib, bosutinib, crizotinib, dabrafenib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, ponatinib, regorafenib, regorafenib M2, regorafenib M5, ruxolitinib, sorafenib, sunitinib, vandetanib). Drugs were arranged in four groups, according to their plasma concentration range: 0...
November 28, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29212964/simple-determination-of-plasma-ponatinib-concentration-using-hplc
#3
Takeo Yasu, Kenji Momo, Shunsuke Kobayashi, Seiichirou Kuroda, Arinobu Tojo
Ponatinib, a novel tyrosine kinase inhibitor marketed in 2016, is a key drug used for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. This study aimed to develop a simple method for determining plasma ponatinib concentration. The analysis required extraction of a 400-μL sample of plasma and precipitation of proteins using an Oasis HLB cartridge. Ponatinib and bosutinib, which is used as an internal standard, were separated by HPLC using a mobile phase of acetonitrile: 0...
December 6, 2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29207163/preclinical-analysis-of-mtor-complex-1-2-inhibition-in-diffuse-intrinsic-pontine-glioma
#4
Patrick C Flannery, John A DeSisto, Vladimir Amani, Sujatha Venkataraman, Rakeb T Lemma, Eric W Prince, Andrew Donson, Erin E Moroze, Lindsey Hoffman, Jean M Mulcahy Levy, Nicholas Foreman, Rajeev Vibhakar, Adam L Green
Diffuse intrinsic pontine glioma (DIPG) is an incurable childhood brain tumor. The mechanistic target of rapamycin (MTOR), a key oncogene, functions as two distinct signaling complexes, MTORC1 and MTORC2. We set out to determine the preclinical efficacy and mechanism of action of MTOR inhibitors in DIPG. We evaluated the MTORC1 inhibitor everolimus and the MTORC1/2 inhibitor AZD2014 in three patient-derived DIPG cell lines using cell culture models. We created dose-response curves for both compounds. We measured phenotypic effects on cell self-renewal, apoptosis, cell cycle, differentiation, senescence, and autophagy...
November 29, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29198338/ponatinib-in-chronic-myeloid-leukemia-cml-consensus-on-patient-treatment-and-management-from-a-european-expert-panel
#5
REVIEW
Martin C Müller, Francisco Cervantes, Henrik Hjorth-Hansen, Jeroen J W M Janssen, Dragana Milojkovic, Delphine Rea, Gianantonio Rosti
Five tyrosine kinase inhibitors (TKIs) are currently approved in the European Union for treatment of chronic myeloid leukemia (CML) and all have considerable overlap in their indications. While disease-specific factors such as CML phase, mutational status, and line of treatment are key to TKI selection, other important features must be considered, such as patient-specific comorbidities and TKI safety profiles. Ponatinib, the TKI most recently approved, has demonstrated efficacy in patients with refractory CML, but is associated with an increased risk of arterial hypertension, sometimes severe, and serious arterial occlusive and venous thromboembolic events...
December 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29197033/establishment-and-proteomic-characterization-of-patient-derived-clear-cell-sarcoma-xenografts-and-cell-lines
#6
Marimu Sakumoto, Rieko Oyama, Mami Takahashi, Yoko Takai, Fusako Kito, Kumiko Shiozawa, Zhiwei Qiao, Makoto Endo, Akihiko Yoshida, Akira Kawai, Tadashi Kondo
Clear cell sarcoma (CCS) is an aggressive mesenchymal malignancy characterized by the unique chimeric EWS-ATF1 fusion gene. Patient-derived cancer models are essential tools for the understanding of tumorigenesis and the development of anti-cancer drugs; however, only a limited number of CCS cell lines exist. The objective of this study was to establish patient-derived CCS models. We established patient-derived CCS models from a 43-yr-old female patient. We prepared the patient-derived xenografts (PDXs) from tumor tissues obtained through biopsy or surgery and isolated stable cell lines from PDXs and the original tumor tissue...
December 1, 2017: In Vitro Cellular & Developmental Biology. Animal
https://www.readbyqxmd.com/read/29175427/therapeutic-drug-monitoring-of-ponatinib-using-a-simple-high-performance-liquid-chromatography-method-in-japanese-patients
#7
Maiko Abumiya, Masatomo Miura, Naoto Takahashi
A simple and highly sensitive high-performance liquid chromatography (HPLC) method was developed for the quantification of ponatinib in human plasma. The developed HPLC method was validated based on International D.S. Food and Drug Administration guidelines. This technique utilized a solid-phase extraction step and required only 200μL plasma for a single analysis. The lower limit of quantification for ponatinib was 1.0ng/mL. Coefficients of variation and accuracies for intra- and interday assays were less than 10...
November 22, 2017: Leukemia Research
https://www.readbyqxmd.com/read/29165716/targeting-bcr-abl-independent-tki-resistance-in-chronic-myeloid-leukemia-by-mtor-and-autophagy-inhibition
#8
Rebecca Mitchell, Lisa E M Hopcroft, Pablo Baquero, Elaine K Allan, Kay Hewit, Daniel James, Graham Hamilton, Arunima Mukhopadhyay, Jim O'Prey, Alan Hair, Junia V Melo, Edmond Chan, Kevin M Ryan, Véronique Maguer-Satta, Brian J Druker, Richard E Clark, Subir Mitra, Pawel Herzyk, Franck E Nicolini, Paolo Salomoni, G Vignir Helgason
Background: Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment...
November 20, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29138996/ichthyosiform-pityriasis-rubra-pilaris-like-eruption-secondary-to-ponatinib-therapy-case-report-and-literature-review
#9
Ariel E Eber, Alyx Rosen, Kate E Oberlin, Alessio Giubellino, Paolo Romanelli
Tyrosine kinase inhibitors have revolutionized the chemotherapy arena as targeted therapies for a multitude of malignancies. They are more selective than conventional chemotherapy, and often elicit fewer systemic adverse events, however toxicities still exist. Cutaneous toxicities are common and their management presents a novel challenge to physicians and patients. Ponatinib is a third-generation tyrosine kinase inhibitor increasingly reported to cause cutaneous eruption. A 50-year-old woman with a history of chronic myelogenous leukemia presented with a 4-month history of worsening atrophic and ichthyosiform pink plaques involving the axillae, thighs and abdomen; red patches were also observed on the cheeks and forehead...
November 14, 2017: Drug Safety—Case Reports
https://www.readbyqxmd.com/read/29132397/kinase-profiling-of-liposarcomas-using-rnai-and-drug-screening-assays-identified-druggable-targets
#10
Deepika Kanojia, Manoj Garg, Jacqueline Martinez, Anand M T, Samuel B Luty, Ngan B Doan, Jonathan W Said, Charles Forscher, Jeffrey W Tyner, H Phillip Koeffler
BACKGROUND: Liposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management. METHODS: Large RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes...
November 13, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29128554/immunomodulatory-effects-of-tyrosine-kinase-inhibitor-in-vitro-and-in-vivo-study
#11
Elena Marinelli Busilacchi, Andrea Costantini, Nadia Viola, Benedetta Costantini, Jacopo Olivieri, Luca Butini, Giorgia Mancini, Ilaria Scortechini, Martina Chiarucci, Monica Poiani, Antonella Poloni, Pietro Leoni, Attilio Olivieri
Pathogenesis of chronic graft-versus-host disease (cGVHD) is incompletely defined, involving donor-derived CD4 and CD8-positive T lymphocytes as well as B cells. Standard treatment is lacking for steroid-dependent/refractory cases; therefore, the potential usefulness of tyrosine kinase inhibitors (TKIs) has been suggested, based on their potent antifibrotic effect. However, TKIs seem to have pleiotropic activity. We sought to evaluate the in vitro and in vivo impact of different TKIs on lymphocyte phenotype and function...
November 8, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29103102/combination-of-emricasan-with-ponatinib-synergistically-reduces-ischemia-reperfusion-injury-in-rat-brain-through-simultaneous-prevention-of-apoptosis-and-necroptosis
#12
Jing Tian, Shu Guo, Heng Chen, Jing-Jie Peng, Miao-Miao Jia, Nian-Sheng Li, Xiao-Jie Zhang, Jie Yang, Xiu-Ju Luo, Jun Peng
Apoptosis and receptor-interacting protein kinase 1/3(RIPK1/3)-mediated necroptosis contribute to the cerebral ischemia/reperfusion (I/R) injury. Emricasan is an inhibitor of caspases in clinical trials for liver diseases while ponatinib could be a potential inhibitor for RIPK1/3. This study aims to investigate the effect of emricasan and/or ponatinib on cerebral I/R injury and the underlying mechanisms. Firstly, we evaluated the status of apoptosis and necroposis in a rat model of cerebral I/R under different conditions, which showed noticeable apoptosis and necroptosis under condition of 2-h ischemia and 24-h reperfusion; next, the preventive or therapeutic effect of emricasan or ponatinib on cerebral I/R injury was tested...
November 4, 2017: Translational Stroke Research
https://www.readbyqxmd.com/read/29072336/mechanisms-of-toxicity-associated-with-six-tyrosine-kinase-inhibitors-in-human-hepatocyte-cell-lines
#13
Cécile Mingard, Franziska Paech, Jamal Bouitbir, Stephan Krähenbühl
Tyrosine kinase inhibitors have revolutionized the treatment of certain cancers. They are usually well tolerated, but can cause adverse reactions including liver injury. Currently, mechanisms of hepatotoxicity associated with tyrosine kinase inhibitors are only partially clarified. We therefore aimed at investigating the toxicity of regorafenib, sorafenib, ponatinib, crizotinib, dasatinib and pazopanib on HepG2 and partially on HepaRG cells. Regorafenib and sorafenib strongly inhibited oxidative metabolism (measured by the Seahorse-XF24 analyzer) and glycolysis, decreased the mitochondrial membrane potential and induced apoptosis and/or necrosis of HepG2 cells at concentrations similar to steady-state plasma concentrations in humans...
October 26, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/29050692/which-tyrosine-kinase-inhibitor-should-we-use-to-treat-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#14
REVIEW
Nicholas J Short, Hagop Kantarjian, Elias Jabbour, Farhad Ravandi
The incorporation of tyrosine kinase inhibitors (TKIs) into chemotherapy regimens has significantly improved the long-term survival of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Successive generations of TKIs with increased potency against BCR-ABL and broader spectrum of activity against ABL kinase domain mutations have led to incremental improvements in the outcomes of patients with this disease. In particular, ponatinib, a potent pan-BCR-ABL TKI capable of overcoming the T315I mutation, holds significant promise in the treatment of Ph+ ALL, although the potential cardiovascular toxicity of this agent remains a concern...
September 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29032022/outcomes-of-newly-diagnosed-chronic-phase-chronic-myeloid-leukemia-following-an-elective-switch-from-second-generation-tyrosine-kinase-inhibitor-to-imatinib
#15
Vamsi K Kota, Jee Hyun Kong, Martha Arellano, Fuad El Rassi, Manila Gaddh, Leonard T Heffner, Elliott F Winton, Anand P Jillella, Morgan L McLemore, H Jean Khoury
The second-generation tyrosine kinase inhibitors (TKIs) (2G-TKIs) dasatinib (DAS) and nilotinib (NIL) yield faster responses in newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) as compared with imatinib (IM); however, long-term safety of these agents is a growing concern. We identified 20 patients with CP-CML diagnosed between August 2013 and October 2016 who initiated 2G-TKIs and were then switched after optimal response at 3 months to IM. Second-generation TKIs initiated were DAS (n = 15), NIL (n = 3), or both sequentially due to intolerance (n = 1)...
September 19, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29027261/prognostic-significance-of-additional-chromosomal-abnormalities-at-the-time-of-diagnosis-in-patients-with-chronic-myeloid-leukemia-treated-with-frontline-tyrosine-kinase-inhibitors
#16
Ahmad Alhuraiji, Hagop Kantarjian, Prajwal Boddu, Farhad Ravandi, Gautam Borthakur, Courtney DiNardo, Naval Daver, Tapan Kadia, Naveen Pemmaraju, Sherry Pierce, Guillermo Garcia-Manero, William Wierda, Srdan Verstovsek, Elias Jabbour, Jorge Cortes
Additional cytogenetic abnormalities (ACA) are considered a high risk feature in chronic myeloid leukemia (CML). However, its prognostic significance at the time of diagnosis in the setting of new tyrosine kinase inhibitors (TKIs) is less well understood. Patients with CML in CP with or without ACA at diagnosis treated with frontline TKIs in prospective clinical trials were analyzed for outcomes. Among 603 patients treated, 29 (5%) had ACA. Patients with ACA included 2 of 72 (2.8%) treated with imatinib 400 mg, 9 of 207 (4...
October 13, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28990873/third-line-treatment-with-second-generation-tyrosine-kinase-inhibitors-dasatinib-or-nilotinib-in-patients-with-chronic-myeloid-leukemia-after-two-prior-tkis-real-life-data-on-a-single-center-experience-along-with-the-review-of-the-literature
#17
Seniz Ongoren, Ahmet Emre Eskazan, Veysel Suzan, Sercan Savci, Isil Erdogan Ozunal, Selin Berk, Fevzi Fırat Yalniz, Tugrul Elverdi, Ayse Salihoglu, Yucel Erbilgin, Sibel Aylin Iseri, Muhlis Cem Ar, Zafer Baslar, Yildiz Aydin, Nukhet Tuzuner, Ugur Ozbek, Teoman Soysal
OBJECTIVES: Newer tyrosine kinase inhibitors (TKIs) (bosutinib, ponatinib) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be utilized as a salvage therapy in patients with chronic myeloid leukemia (CML) who failed two lines (imatinib → nilotinib or imatinib → dasatinib) of TKI therapy. However, these TKIs are not available in many countries and not all patients can undergo allo-HSCT. METHODS: In this study, CML patients who received dasatinib or nilotinib as a third-line treatment were retrospectively evaluated...
October 9, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28983061/bcr-abl1-compound-mutants-display-differential-and-dose-dependent-responses-to-ponatinib
#18
Konstantin Byrgazov, Chantal Blanche Lucini, Peter Valent, Oliver Hantschel, Thomas Lion
No abstract text is available yet for this article.
October 5, 2017: Haematologica
https://www.readbyqxmd.com/read/28978841/treatment-of-relapsed-or-refractory-acute-lymphoblastic-leukemia
#19
Kiyotoshi Imai
Most patients with adult acute lymphoblastic leukemia (ALL) undergo relapse, despite the achievement of complete remission with chemotherapy. Among patients with relapsed or refractory ALL, remission rates are 18-44% with the use of standard salvage chemotherapy, but the duration of remission is short. A major goal in this population is to induce remission with a sufficient duration to prepare for stem cell transplantation. The poor outcomes and lack of durable responses seen with conventional chemotherapy have led to the development of several novel agents, including clofarabine and nelarabine...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28978814/erratum-pharmacological-characteristics-and-clinical-outcomes-of-ponatinib-iclusig-%C3%A2-a-third-generation-tyrosine-kinase-inhibitor
#20
(no author information available yet)
No abstract text is available yet for this article.
2017: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
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