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Poe-Hirr Hsyu, Daniela Soriano Pignataro, Kyle Matschke
PURPOSE: Bosutinib is an oral, dual Src and Abl tyrosine kinase inhibitor (TKI) approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia resistant or intolerant to prior TKI therapy. Bosutinib is primarily metabolized by cytochrome P450 (CYP) 3A4, suggesting drug interaction potential with other CYP3A4 modulators. This open-label, randomized, 2-sequence, 2-period crossover study assessed the effect of single-dose aprepitant, a moderate CYP3A4 inhibitor, on the single-dose pharmacokinetic profile of oral bosutinib 500 mg...
October 7, 2016: European Journal of Clinical Pharmacology
Poe-Hirr Hsyu, Daniela Soriano Pignataro, Kyle Matschke
PURPOSE: Bosutinib, a dual Src and Abl tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, demonstrated concentration-dependent inhibitory effects on P-glycoprotein (P-gp)-mediated digoxin efflux in vitro, suggesting that bosutinib may inhibit P-gp substrates. The effect of bosutinib on dabigatran etexilate mesylate (EM) absorption, a P-gp substrate, was evaluated. METHODS: In this open-label, randomized, single-dose, one-cohort, two-sequence, two-period crossover study, healthy, fed subjects received dabigatran EM (150 mg × 1 orally) alone or 1 h after receiving bosutinib tablets (100 mg × 5 orally)...
October 7, 2016: European Journal of Clinical Pharmacology
Stephanie Bauer, Susan Buchanan, Irene Ryan
Several tyrosine kinase inhibitors (TKIs) are now approved for the treatment of chronic myeloid leukemia in chronic phase. The efficacy of these drugs has been repeatedly demonstrated, as has their tolerability in most patients. However, late and chronic toxicities become an important issue for many patients facing long-term TKI exposure. For patients on long-term imatinib, gastrointestinal events, fluid retention, muscle cramps, fatigue, and hepatotoxicity are among the most common and most clinically relevant adverse events (AEs)...
January 2016: Journal of the Advanced Practitioner in Oncology
Brian B Hasinoff, Daywin Patel, Xing Wu
Five clinically approved BCR-ABL1-targeted tyrosine kinase inhibitors (bosutinib, dasatinib, imatinib, nilotinib, and ponatinib) used for treating chronic myelogenous leukemia have been studied in a neonatal rat myocyte model for their relative ability to induce myocyte damage. This was done in order to determine if kinase inhibitor-induced myocyte damage was a consequence of inhibiting ABL1 (on-target effects), or due to a lack of kinase selectivity (off-target effects) since previous studies have come up with conflicting conclusions about whether imatinib-induced cardiotoxicity results directly from inhibition of ABL1...
September 30, 2016: Cardiovascular Toxicology
Lauren Caldemeyer, Luke P Akard
With BCR-ABL1 tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib, many patients with chronic myeloid leukemia in chronic phase (CML-CP) can expect to live near-normal life spans. Current treatment recommendations of the National Comprehensive Cancer Network and the European LeukemiaNet state that patients with CML-CP should remain on TKI therapy indefinitely. However, there is increasing evidence from clinical trials that some patients with sustained deep molecular responses may be able to achieve treatment-free remission (TFR), whereby they can suspend TKI therapy without losing previously achieved responses...
December 2016: Leukemia & Lymphoma
Ronit Gurion, Pia Raanani, Liat Vidal, Avi Leader, Anat Gafter-Gvili
BACKGROUND: The choice of a specific tyrosine kinase inhibitor (TKI) as first line treatment in chronic myeloid leukemia (CML) is complex and influenced by multiple factors. We published a meta-analysis examining the role of newer TKIs as first line treatment in chronic phase CML. In view of the recently published data, we decided to update it. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials comparing first line treatment with imatinib to the newer TKIs (nilotinib, dasatinib, bosutinib and ponatinib)...
August 25, 2016: Acta Oncologica
Jorge E Cortes, Hanna J Khoury, Hagop M Kantarjian, Jeff H Lipton, Dong-Wook Kim, Philippe Schafhausen, Ewa Matczak, Eric Leip, Kay Noonan, Tim H Brümmendorf, Carlo Gambacorti-Passerini
Bosutinib is a Src/Abl tyrosine kinase inhibitor (TKI) indicated for adults with Ph+ chronic myeloid leukemia (CML) resistant/intolerant to prior TKIs. This long-term update of an ongoing phase 1/2 study evaluated the efficacy and safety of third-/fourth-line bosutinib in adults with chronic phase (CP) CML. Median durations of treatment and follow-up were 8.6 (range, 0.2-87.7) months and 32.7 (0.3-93.3) months, respectively. Cumulative confirmed complete hematologic response (cCHR) and major cytogenetic response (MCyR) rates were 74% (95% CI, 65%-81%) and 40% (31%-50%), respectively; Kaplan-Meier (K-M) probability of maintaining cCHR or MCyR at 4 years was 63% (95% CI, 50%-73%) and 69% (52%-81%)...
August 17, 2016: American Journal of Hematology
Lanier Heyburn, Michaeline L Hebron, Jacqueline Smith, Charisse Winston, John Bechara, Zhaoxia Li, Irina Lonskaya, Mark P Burns, Brent Harris, Charbel E-H Moussa
The trans-activating response DNA/RNA binding protein (TDP)-43 pathology is associated with many neurodegenerative diseases via unknown mechanisms. Here, we use a transgenic mouse model overexpressing human wild-type neuronal TDP-43 to study the effects of TDP-43 pathology on glutamate metabolism and synaptic function. We found that neuronal TDP-43 overexpression affects synaptic protein expression, including Synapsin-1 and alters surrounding astrocytic function. TDP-43 over-expression is associated with an increase in glutamate and GABA and reduction of glutamine and aspartate levels, indicating impairment of pre-synaptic terminal...
August 10, 2016: Journal of Neurochemistry
Xiyan Yu, Tong Wang, Ying Lou, Yanwen Li
The epidermal growth factor receptor 2 (HER2) has been established as an important target of HER2-positive lung cancer, but somatic mutations in HER2 kinase domain are frequently observed that may cause drug resistance and sensitivity for tyrosine kinase inhibitors (TKIs). In this study, the response profile of 14 small-molecule TKIs upon 11 clinical HER2 mutations was investigated systematically using a synthetic strategy that integrated in silico analysis and in vitro assay to explore the structural basis, energetic property and biological implication underlying the intermolecular interactions of TKIs with wild-type and variant HER2...
January 2016: Molecular Informatics
Vijaya L Damaraju, Dwayne Weber, Michelle Kuzma, Carol E Cass, Michael B Sawyer
Human nucleoside transporters (hNTs) mediate cellular influx of anticancer nucleoside drugs, including cytarabine, cladribine, and fludarabine. BCR-ABL tyrosine kinase inhibitors (TKIs) imatinib and dasatinib inhibit fludarabine and cytarabine uptake. We assessed interactions of bosutinib, dasatinib, imatinib, nilotinib, and ponatinib with recombinant hNTs (hENT1, 2; hCNT1, -2, and -3) produced individually in yeast Saccharomyces cerevisiae Nilotinib inhibited hENT1-mediated uridine transport most potently (IC50 value, 0...
September 2, 2016: Journal of Biological Chemistry
Dawn M Wetzel, Emma L Rhodes, Shaoguang Li, Diane McMahon-Pratt, Anthony J Koleske
Leishmaniasis is a devastating disease that disfigures or kills nearly two million people each year. Establishment and persistence of infection by the obligate intracellular parasite Leishmania requires repeated uptake by macrophages and other phagocytes. Therefore, preventing uptake could be a novel therapeutic strategy for leishmaniasis. Amastigotes, the life cycle stage found in the human host, bind Fc receptors and enter macrophages primarily through immunoglobulin-mediated phagocytosis. However, the host machinery that mediates amastigote uptake is poorly understood...
August 15, 2016: Journal of Cell Science
Danilo Perrotti, Giovannino Silvestri, Lorenzo Stramucci, Justine Yu, Rossana Trotta
The use of imatinib, second and third generation ABL tyrosine kinase inhibitors (TKI) (i.e. dasatinib, nilotinib, bosutinib and ponatinib) made CML a clinically manageable and, in a small percentage of cases, a cured disease. TKI therapy also turned CML blastic transformation into a rare event; however, disease progression still occurs in those patients who are refractory, not compliant with TKI therapy or develop resistance to multiple TKIs. In the past few years, it became clear that the BCR-ABL1 oncogene does not operate alone to drive disease emergence, maintenance and progression...
June 14, 2016: Current Drug Targets
David Gómez-Almaguer, Olga G Cantú-Rodríguez, Cesar H Gutiérrez-Aguirre, Guillermo J Ruiz-Argüelles
OBJECTIVES: This article reviews clinical experiences in the treatment of chronic myeloid leukemia (CML) in an environment of limited resources. METHODS: We reviewed recent publications on Pub med and abstracts from mayor congresses relevant to the disease. RESULTS: CML is a hematological neoplasm observed more frequently in adults, regardless of their socioeconomic status. Until recently, available treatments improved patients' quality of life but did not modify survival...
May 24, 2016: Hematology (Amsterdam, Netherlands)
Ah-Rong Nam, Ji-Won Kim, Ji Eun Park, Ju-Hee Bang, Mei Hua Jin, Kyung-Hun Lee, Tae-Yong Kim, Sae-Won Han, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang
Src, a nonreceptor tyrosine kinase, is involved in a number of cancer-related signaling pathways and aberrantly activated in biliary tract cancer (BTC). This study aimed to elucidate the potential role of Src as a therapeutic target in BTC. We tested bosutinib, an orally active c-Src/Abl kinase inhibitor, alone or in combination with cytotoxic agents using 9 human BTC cell lines: SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079, SNU-1196, HuCCT1, TFK-1, and EGI-1. Of these, SNU-308 and SNU-478 were relatively sensitive to bosutinib...
July 2016: Molecular Cancer Therapeutics
Makoto Tahara, Atsushi Shibata, Shinya Katsura
No abstract text is available yet for this article.
May 2016: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
S Deb, C Sjöström, A Tharmakulanathan, N Boknäs, K Lotfi, S Ramström
INTRODUCTION: During the last two decades, Bcr-Abl tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myelogenous leukemia (CML), and are now considered standard treatment for this disease. However, TKIs can induce serious hemostatic side effects including cardiovascular disease and bleeding disorders. Blood platelet aggregation and formation of pro-coagulant platelets are important to allow a well-balanced hemostatic response. Therefore, a detailed understanding of what effect different TKIs exert on platelets and hemostasis could help to understand if there are differences of importance to minimize the risk of bleeding complications in treated patients...
April 2016: Thrombosis Research
Susan Fajardo, Felicia Zook, Emily Dotson
PURPOSE: The oral oncology medications used in the treatment of chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, and non-Hodgkin's lymphoma are reviewed, and the specialty pharmacy services at three large academic medical centers are described. SUMMARY: More than one dozen oral oncology medications are being used for hematologic malignancies and afford patients increased convenience and the potential to improve their quality of life. These agents include ibrutinib, idelalisib, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, thalidomide, lenalidomide, pomalidomide, panobinostat, ixazomib, and vorinostat...
June 1, 2016: American Journal of Health-system Pharmacy: AJHP
Richat Abbas, Poe-Hirr Hsyu
Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disorder. Bosutinib is an oral, once-daily SRC/ABL tyrosine kinase inhibitor with very potent inhibitory activity. Bosutinib is effective against all phases of intolerant or resistant Philadelphia chromosome-positive CML that do not harbor the T315I or V299LABL kinase domain mutations. Peak plasma concentrations of bosutinib occur at 4-6 h following oral administration, and dose-proportional increases in exposure are observed at doses ranging from 200 to 800 mg...
October 2016: Clinical Pharmacokinetics
Constance Baer, Wolfgang Kern, Sarah Koch, Niroshan Nadarajah, Sonja Schindela, Manja Meggendorfer, Claudia Haferlach, Torsten Haferlach
Chronic myeloid leukemia cells acquire resistance to tyrosine kinase inhibitors through mutations in the ABL1 kinase domain. The T315I mutation mediates resistance to imatinib, dasatinib, nilotinib and bosutinib, whereas sensitivity to ponatinib remains. Mutation detection by conventional Sanger sequencing requires 10%-20% expansion of the mutated subclone. We studied the T315I mutation development by ultra-deep sequencing on the 454 XL+ platform (Roche) in comparison to Sanger sequencing. By ultra-deep sequencing, mutations were detected at loads of 1%-2%...
July 2016: Haematologica
Seongseok Yun, Nicole D Vincelette, Jennifer M Segar, Yimin Dong, Yang Shen, Dong-Wook Kim, Ivo Abraham
BACKGROUND: BCR-ABL1 tyrosine kinase inhibitors (TKIs) have significantly improved the survival outcomes for patients with chronic myeloid leukemia (CML). In addition to imatinib, 3 newer generation TKIs (NG-TKIs) have been approved as first-line treatment of chronic phase (CP)-CML. These have been preferably used in patients with CP-CML with a high Sokal or Hasford risk score. We performed a systematic review and meta-analysis to compare the outcomes with NG-TKIs as a category versus imatinib in patients with newly diagnosed CP-CML and to indirectly compare the efficacy of NG-TKIs among each other...
June 2016: Clinical Lymphoma, Myeloma & Leukemia
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