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Fausto Castagnetti, Francesco Di Raimondo, Antonio De Vivo, Antonio Spitaleri, Gabriele Gugliotta, Francesco Fabbiano, Isabella Capodanno, Donato Mannina, Marzia Salvucci, Agostino Antolino, Roberto Marasca, Maurizio Musso, Monica Crugnola, Stefana Impera, Elena Trabacchi, Caterina Musolino, Francesco Cavazzini, Giuseppe Mineo, Patrizia Tosi, Carmela Tomaselli, Michele Rizzo, Sergio Siragusa, Miriam Fogli, Riccardo Ragionieri, Alessandro Zironi, Simona Soverini, Giovanni Martinelli, Michele Cavo, Paolo Vigneri, Fabio Stagno, Gianantonio Rosti, Michele Baccarani
Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion-exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion-exclusion criteria do not exist and the treatment outcome does not only depend on the choice of first-line TKI, but also on second- and third-line TKIs...
October 22, 2016: American Journal of Hematology
Hye Seon Kang, Chin Kook Rhee, Hea Yon Lee, Hyoung Kyu Yoon, Soon Seok Kwon, Sook Young Lee
Background/Aims: Inhaled corticosteroids are the most effective treatment currently available for asthma, but their beneficial effect against airway remodeling is limited. The tyrosine kinase inhibitor nilotinib has inhibitory activity against c-kit and the platelet-derived growth factor receptor. We compared the effects of fluticasone and nilotinib on airway remodeling in a chronic asthma model. We also examined whether co-treatment with nilotinib and fluticasone had any synergistic effect in preventing airway remodeling...
October 20, 2016: Korean Journal of Internal Medicine
Qie He, Junfeng Zhu, David Dingli, Jasmine Foo, Kevin Zox Leder
Over the past decade, several targeted therapies (e.g. imatinib, dasatinib, nilotinib) have been developed to treat Chronic Myeloid Leukemia (CML). Despite an initial response to therapy, drug resistance remains a problem for some CML patients. Recent studies have shown that resistance mutations that preexist treatment can be detected in a substantial number of patients, and that this may be associated with eventual treatment failure. One proposed method to extend treatment efficacy is to use a combination of multiple targeted therapies...
October 2016: PLoS Computational Biology
M Herbrink, N de Vries, H Rosing, A D R Huitema, B Nuijen, J H M Schellens, J H Beijnen
BACKGROUND: A liquid chromatography/tandem mass spectrometry assay was developed to facilitate therapeutic drug monitoring (TDM) for 10 anticancer compounds (dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, and vemurafenib) and the active metabolite, N-desethyl-sunitinib. METHODS: The TDM assay is based on reversed-phase chromatography coupled with tandem mass spectrometry in the positive ion mode using multiple-reaction monitoring for analyte quantification...
October 5, 2016: Therapeutic Drug Monitoring
Thomas O'Hare
No abstract text is available yet for this article.
October 15, 2016: Cancer Research
Susannah O'Sullivan, Mei Lin Tay, Jian-Ming Lin, Usha Bava, Karen Callon, Jillian Cornish, Dorit Naot, Andrew Grey
Nilotinib and imatinib are tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). In vitro, imatinib and nilotinib inhibit osteoclastogenesis, and in patients they reduce levels of bone resorption. One of the mechanisms that might underlie these effects is an increase in the production of osteoprotegerin (OPG). In the current work we report that platelet-derived growth factor receptor beta (PDGFRβ) signaling regulates OPG production in vitro...
2016: PloS One
Ayala Gover-Proaktor, Galit Granot, Saar Shapira, Oshrat Raz, Oren Pasvolsky, Arnon Nagler, Dorit L Lev, Aida Inbal, Ido Lubin, Pia Raanani, Avi Leader
Tyrosine kinase inhibitors (TKIs) have revolutionized the prognosis of chronic myeloid leukemia. With the advent of highly efficacious therapy, the focus has shifted toward managing TKI adverse effects, such as vascular adverse events (VAEs). We used an in vitro angiogenesis model to investigate the TKI-associated VAEs. Our data show that imatinib, nilotinib, and ponatinib reduce human umbilical vein endothelial cells (HUVECs) viability. Pharmacological concentrations of ponatinib induced apoptosis, reduced migration, inhibited tube formation of HUVECs, and had a negative effect on endothelial progenitor cell (EPC) function...
October 12, 2016: Leukemia & Lymphoma
Noriyoshi Iriyama, Yoshihiro Hatta, Masami Takei
It has been shown that an increase in cytotoxic lymphocyte counts in the peripheral blood occurs rapidly after taking dasatinib, but the underlying mechanism is not yet elucidated. To investigate the influence of dasatinib on signal transduction pathways, we investigated the changes in JAK-STAT, mitogen-activated protein kinase (MAPK), and AKT in cytotoxic lymphocytes, including natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), before and after dasatinib treatment in chronic myeloid leukemia patients...
October 10, 2016: Cancer Medicine
Sayaka Sasaoka, Toshinobu Matsui, Yuuki Hane, Junko Abe, Natsumi Ueda, Yumi Motooka, Haruna Hatahira, Akiho Fukuda, Misa Naganuma, Shiori Hasegawa, Yasutomi Kinosada, Mitsuhiro Nakamura
Long QT syndrome (LQTS) is a disorder of the heart's electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal. There have been no previous reports on the time-to-onset for LQTS based on data from spontaneous reporting systems. The aim of this study was to assess the time-to-onset of LQTS according to drug treatment. We analyzed the association between 113 drugs in 37 therapeutic categories and LQTS including TdP using data obtained from the Japanese Adverse Drug Event Report database...
2016: PloS One
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
Muhammad Wasif Saif, Melissa Hennessey Smith, Antonia Maloney, Robert B Diasio
Imatinib, an orally administered protein-tyrosine kinase inhibitor (TKI) is indicated for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). Severe hepatotoxicity associated with imatinib is rare, and relationship to polymorphism of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) expression and related frequency of hyperbilirubinemia or toxicity are not well known. We present a case series patients who developed hyperbilirubinemia while on oral administration imatinib for treatment of GIST...
October 2016: Annals of Gastroenterology: Quarterly Publication of the Hellenic Society of Gastroenterology
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
Shinichiro Kawamoto, Katsuya Yamamoto, Masanori Toyoda, Kimikazu Yakushijin, Hiroshi Matsuoka, Hironobu Minami
Constitutional translocations that coincide with t(9;22)(q34;q11.2) may lead to unnecessary treatments in chronic myeloid leukemia (CML) patients, as, under the standard criteria, a diagnosis of CML with additional chromosomal abnormalities indicates an accelerated phase (AP). In the present report, a 47-year-old male had pain in the right foot due to gout. Peripheral blood examination showed leukocytosis with left shift. Bone marrow aspiration revealed myeloid hyperplasia with megakaryocytosis. RT-PCR revealed the major BCR-ABL fusion transcript, and CML in the chronic phase was diagnosed, followed by nilotinib treatment...
September 29, 2016: International Journal of Hematology
Hisae Nishioka, Norie Tooi, Takehisa Isobe, Norio Nakatsuji, Kazuhiro Aiba
Alzheimer's disease (AD) is the most common form of dementia. Cellular AD models derived from human pluripotent stem cells are promising tools in AD research. We recently developed human embryonic stem cell-derived AD models which overexpress mutant Presenilin1 genes, and which exhibit AD phenotypes, including synaptic dysfunction. In this study, we found that our AD models showed reduced levels of RAB3A and SV2B proteins in the pre-synapses, which is a possible cause of electrophysiological abnormalities. Through the screening of chemical compounds using our AD models, we have identified Aβ peptide inhibitors which decrease the concentration of Aβ in culture supernatant...
2016: Scientific Reports
Akihito Fujimi, Hiroki Sakamoto, Yuji Kanisawa, Shinya Minami, Yasuhiro Nagamachi, Naofumi Yamauchi, Soushi Ibata, Junji Kato
A 55-year-old man with several comorbidities including idiopathic interstitial pneumonia under long-term corticosteroid therapy, longstanding myocardial infarction, chronic heart failure, paroxysmal atrial fibrillation, gastro-esophageal reflux disease, constipation, and history of paralytic ileus, was diagnosed with chronic myelogenous leukemia (CML) in the chronic phase. He also tested positive for anti-topoisomerase I antibodies without clinical diagnosis of any connective tissue disease, including systemic sclerosis...
September 16, 2016: Clinical Journal of Gastroenterology
Shilpi Khetarpal, Apra Sood, Steven D Billings
Keratosis pilaris (KP) is a disorder of follicular keratinization that is characterized by keratin plugs in the hair follicles with surrounding erythema. A 46-year-old man with chronic myelogenous leukemia (CML) was started on nilotinib, a second generation tyrosine kinase inhibitor (TKI). Two months later the patient noticed red bumps on the skin and patchy hair loss on the arms, chest, shoulders, back, and legs. Cutaneous reactions to nilotinib are the most frequent non-hematologic adverse effects reported...
2016: Dermatology Online Journal
Dominick Latremouille-Viau, Annie Guerin, Roy Nitulescu, Patrick S Gagnon, George J Joseph, Lei Chen
OBJECTIVE: To compare treatment patterns and economic outcomes of dasatinib and nilotinib as 1st-line therapies for chronic myeloid leukemia (CML). METHODS: Adult CML patients initiated on first-line dasatinib or nilotinib in 2010-2014 were identified from two large US administrative claims databases. Treatment patterns, tyrosine kinase inhibitor (TKI) adherence and healthcare resource utilization (HRU) and costs were measured from the 1st-line TKI initiation (index date) to the end of follow-up...
September 7, 2016: Journal of Medical Economics
Gyöngyi Kirschner, Bernadett Balla, János Kósa, Péter Horváth, Andrea Kövesdi, Gergely Lakatos, István Takács, Zsolt Nagy, Bálint Tóbiás, Kristóf Árvai, Péter Lakatos
Tyrosine kinase inhibitors are widely used for treatment of certain oncohematological diseases. Several clinical studies have confirmed that specific BCR-ABL tyrosine kinase inhibitors alter the physiological process of bone tissue in a complex and unclearly identified manner. Since these treatments are being given to more and more patients, and the therapy takes decades or lasts even lifelong, it is justifiable to obtain more detailed knowledge of the molecular background of these mechanisms. In this article the authors summarize preliminary research results and human clinical observations on imatinib and nilotinib which are related to bone metabolism, and present the results of their own experiments in in vitro osteoblast cultures...
September 2016: Orvosi Hetilap
Shinya Kimura
ABL tyrosine kinase inhibitors (TKIs) dramatically improves chronic myeloid leukemia (CML) prognosis and most CML patients are now able to lead lives that are equivalent to those of healthy individuals. However, high cost to CML patients of long-term treatment and adverse effects (AEs) remain problems. At the setout, a clinical study involving the discontinuation of imatinib was conducted in France. Then, several stop studies of first-generation (imatinib) and second-generation ABL TKIs (dasatinib, nilotinib), which induce earlier response than imatinib, have also been started...
2016: Stem Cell Investigation
M K Angelopoulou, J V Asimakopoulos, Z Galani, G Levidou, M Roumelioti, T P Vassilakopoulos, P Korkolopoulou, P Panayiotidis
No abstract text is available yet for this article.
2016: Blood Cancer Journal
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